Prospective Phase II Pilot Study, Assessing Imaging Performance of 89Zirconium-labelled Girentuximab (89Zr-TLX250) PET-CT (Positron Emission Tomography/Computerized Tomography) in Metastatic Triple Negative Breast Cancer Patients
Phase: PHASE2
Conditions: Triple Negative Breast Cancer
Sponsor: Institut Cancerologie de l'Ouest

Short Title : 
 
OPALESCENCE 
Ref ICO : 
 
ICO-2020-25 
N° EudraCT : 
 
2020-003805-71 
 
 
  
OPALESCENCE 
zircOn PET-CT imAging TLX mEtaStatiC triplE Negative CancEr 
 
ʺProspective feasibility  pilot study, assessing imaging performance of 89Zirconium-
labelled Girentuximab (89Zr-TLX250) PET-CT in metastatic triple negative breast 
cancer patientsʺ 
 
 
 
N° EUDRACT: 
2020-003805-71 
Ref ICO: 
 
ICO-2020-25 
Study type:   
RIPH – cat.1 (Médicament) 
 
 
 
Investigator 
Coordinator 
 
Dr Caroline ROUSSEAU, MD 
Nuclear Medicine Department  
Institut de Cancérologie de l’Ouest 
Phone: +33 2 40 67 99 31 ; Fax : +33 2 40 67 97 87 
Email : caroline.rousseau@ico.unicancer.fr 
 
 
 
Methodologist 
 
Dr Loïc Campion, MD 
Biometry Department 
Institut de Cancérologie de l’Ouest (ICO) 
Phone : +33 2 40 67 99 00 ; Fax : +33 2 40 67 97 87 
Email : loic.campion@ico.unicancer.fr 
 
 
Sponsor : 
 
Institut de Cancérologie de l’Ouest 
Service Promotion de la Recherche Clinique (DRC) 
Boulevard Jacques Monod - 44805 SAINT HERBLAIN CEDEX  
 
Contact : Nadia ALLAM, PhD Project Manager 
Phone : +33 2 40 67 98 26 ; Fax :  
+33 2 40 67 97 87 
Email :  nadia.allam@ico.unicancer.fr 
 
 
 
 

 
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APPROVAL AND PROTOCOL SIGNATURE 
 SPONSOR REPRESENTATIVE 
 The sponsor undertakes to ensure that this study is conducted in accordance with this protocol, and all 
applicable legislation. 
SPONSOR 
Raphaëlle Charron-Bighetti 
Deputy Director of Research 
Institut de Cancérologie de l’Ouest (ICO) 
 
Date: 
 
 
 
Signature: 
 
 COORDINATING INVESTIGATOR FOR STUDY 
I have read all the pages of the clinical trial protocol of which Institut de Cancérologie de l’Ouest is the sponsor. I 
confirm that it contains all the information required to conduct the trial. I undertake to carry out the study in 
accordance with the protocol and the terms and conditions defined therein. . I undertake to conduct the trial in 
accordance with : 
• 
La Déclaration d’Helsinki de l’AMM, 
• 
Les ICH Guidelines for Good Clinical Practices (E6) 
• 
Le Code de la Santé Publique, 
• 
La Loi n°2004-806 du 9 août 2004 relative à la politique de santé publique portant notamment 
transposition de la directive européenne n°2001/20/CE du 4 avril 2001 et la loi n°2006-450 du 18 avril 
2006 
• 
La Loi Jardé n°2012-300 du 12 mars 2012 (décret d’application du 16 novembre 2016) concernant la 
recherche sur la personne humaine) 
• 
La Loi n°2011-814 du 7 juillet 2011 relative à la bioéthique, 
• 
La Loi n° 78-17 du 6 janvier 1978 relative à l’informatique aux fichiers et aux libertés, modifiée notamment 
par la Loi n° 204-801 du 6 août 2004 et la loi n°2018-493 du 20 juin 2018, dans sa version en vigueur au 
moment de la réalisation de l’Essai. 
• 
Le Règlement (UE) n°2016/679 du 27 avril 2016 relatif à la protection des données personnelles (RGPD). 
 
I also undertake to ensure that investigators and other qualified members of my team have access to copies of this 
protocol and the trial conduct documents to enable them to work in accordance with the protocol guidelines. 
 
Investigator 
Coordinator  
Name:  
 
Dr Caroline ROUSSEAU 
 
Date: 
 
 
Signature: 
 
Principal 
Investigator  
Name and centre:   
 
 
 
Date: 
Signature: 
 
 

 
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CLINICAL TRIAL AUTHORIZATION 
PROTOCOL OPALESCENCE  
 
ʺProspective feasibility pilot study, assessing imaging performance of 89Zirconium-labelled Girentuximab 
(89Zr-TLX250) PET-CT in metastatic triple negative breast cancer patientsʺ 
 
CLINICAL TRIAL AUTHORIZATION 
Agence 
Nationale 
de 
Sécurité 
du 
Médicament et des Produits de Santé 
(ANSM): 
Date of authorization: 12/03/2021 
Ref. ANSM (IDRCB) : MEDAECPP-2021-01-00009_2020-003805-71  
Ethics committee : 
CPP SUD EST VI (CLERMONT-FERRAND) 
Date of approval: 23/04/2021 
Ref. CPP: Ref. CPP: 21.01.13.57453-AU_1682  
 
SPONSOR REPRESENTATIVE 
Dr Caroline ROUSSEAU, MD 
Coordinator 
Nuclear Medicine Department  
Institut de Cancérologie de l’Ouest 
Phone: +33 2 40 67 99 31 ; Fax : +33 2 40 67 97 87 
Email :  caroline.rousseau@ico.unicancer.fr 
Dr Loïc Campion, MD 
Methodologist 
Biometry Department 
Institut de Cancérologie de l’Ouest (ICO) 
Phone : +33 2 40 67 99 00 ; Fax : +33 2 40 67 97 87 
Email :  
loic.campion@ico.unicancer.fr 
 
Nadia ALLAM, PhD 
Project Manager  
Service Promotion de la Recherche Clinique (DRCI) 
Phone : 
+33 2 40 67 98 26 ; Fax :  +33 2 40 67 97 87 
Email :  
nadia.allam@ico.unicancer.fr 
Enrolment 
Enrolment is made online, directly via the eCRF. 
In case of problem, please write to the following email addresses, indicating the 
protocol name in the subject line of the email:  
promotionRC@ico.unicancer.fr  and datamanagement@ico.unicancer.fr 
Pharmacovigilance for ICO 
Anne MILLARET 
Sending of notifications 
Reception and management of notifications : 
Phone :  +33 9 83 77 53 07 
Fax :  
+33 9 81 40 42 80 
E-mail :  
anne.millaret@ctvigilance.fr 
Reception of notifications : 
Phone :  +33 2 40 67 99 08 
E-mail :  
drci.pv@ico.unicancer.fr 
 
 
 

 
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PROTOCOL SYNOPSIS 
 
 
The purpose of this study is to evaluate the use of 89Zr-labeled girentuximab (89Zr-TLX250) as a novel, carbonic 
anhydrase IX (CAIX) targeted PET/CT tracer for the imaging of metastatic triple negative breast cancer (TNBC) 
patients. 
 
TNBC patients are known to be rapidly progressive and have a poor prognosis. This poor prognosis is due to 
the lack of common breast cancer targets in TNBC.  As TNBC expresses CAIX, we plan to evaluate CAIX 
targeting by using a radiolabeled monoclonal antibody that recognizes carbonic anhydrase IX (CAIX) (89Zr- 
girentuximab otherwise known as 89Zr-TLX250).  Previous and ongoing studies have demonstrated the 
potential application of 89Zr-TLX250 as a new PET/CT imaging tracer for the detection of renal cancer. 
 
After establishing the TNBC targeting properties of the 89Zr-TLX250 PET/CT imaging tracer, it should be 
interesting to develop a new targeted therapy using TLX250- radiolabeled with a therapeutic radionuclide 
such as 177Lutétium. 
 
 
 
 

 
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ABBREVIATIONS AND DEFINITION OF TERMS 
The following abbreviations and special terms are used in this study Clinical Study Protocol. 
Abbreviation or special 
term 
Explanation 
18F 
Fluor-18 
124I 
Iodine-124 
111In 
Indium-111 
177Lu 
Lutetium-177 
89Zr 
Zirconium-89 
ADL 
Activities of Daily Living 
AE 
Adverse event 
ALAT 
Alanine aminotransferase 
ANSM 
French Health Authority 
ASAT 
Aspartate aminotransferase 
ATZ 
Acetazolamide 
Β-HCG 
Beta human chorionic gonadotropin 
BP 
Blood Pressure 
CA IX 
Carbonic anhydrase IX 
CA 15-3 
Cancer antigen 15-3 
CEA 
carcinoembryonic antigen 
CPP 
French Ethics Committee 
CT 
Computed tomography 
DSUR 
Development Safety Update Reports 
eCRF 
Electronic case report form 
EMA 
European Medicines Agency 
ER 
Estrogen Receptor 
EOS 
End Of Study 
EVCTM 
EudraVigilance Clinical Trial Module 
FDG 
Fluorodésoxyglucose 
FU 
Follow up 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
GLP 
Good Laboratory Practice 
HACA 
Human Anti-Chimeric Antibodies 
HER 2 
human Epidermal growth factor Receptor 2 
HIF1α 
Hypoxia-Inducible Factor 1-alpha 
HSA 
Human Serum Albumin 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IHC 
ImmunoHistoChemistry 
IV 
Intravenous(ly) 
mAb 
Monoclonal antibody 
MedDRA 
Medical Dictionary for Regulatory Activities 
MBq 
Mega Becquerel 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events  

 
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Abbreviation or special 
term 
Explanation 
PD-L1 
Programmed death-ligand 1 
PET 
Positron-emission tomography 
PK 
Pharmacokinetic(s) 
PR 
Progesterone Receptor 
PTX 
Paclitaxel 
SAE 
Serious adverse event 
SID 
Subject identification 
SUSAR 
Suspected unexpected serious adverse reaction 
SUV 
Standardized uptake value 
TEAE 
Treatment-emergent adverse event 
TNBC 
Triple Negative Breast Cancer 
UAE 
Unexpected Adverse Event 
WB 
Whole Body 
WHO 
World Health Organization 
 
 
 
 

 
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HISTORY OF PROTOCOLE AMENDMENTS 
 
 
 
Version number / 
Date  
(after amendment) 
Justifications of amendment  
Initial authorisation 
V1.2 du 29/03/2021 
Initial authorized version 
Substantial Amendment 1 
V2 du 21/06/2022 
18-month extension of the recruitment period 
Inclusion criteria 4 modified 
 
 
 
 
 
 
 
 
 
 
 
 

 
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TRIAL CALENDAR 
 
NUMBER OF EXPECTED PATIENTS 
12 patients 
DURATION OF ENROLMENT PERIOD : 
30 months 
DURATION OF PROCEDURE / DURATION OF FOLLOW-UP : 
5 days / 3 months 
MAXIMUM TIME OF PARTICIPATION PER PATIENT : 
4 months (including approximately 1 month 
for the inclusion assessment) 
GLOBAL DURATION OF THE TRIAL : 
33 months 
END OF THE CLINICAL TRIAL : 
Last visit of the last enrolled patient 
 
 
 
CONSIDERED DURATION UNTIL THE ANALYSIS OF THE 
PRIMARY OBJECTIVE :  
45 months (33 + 12 months data analysis) 
INTERIM ANALYSIS : 
NA 
 
 
 

 
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SCHEDULE OF STUDY ASSESSMENTS 
 
Visit 
Screening 
89Zr- Girentuximab PET/CT 
FU # 1 
End of 
Study  
Day 
-30 to -1 
0 
1 
3 
5(f) 
7 
30  
90  
Written informed consent 
X 
 
 
 
 
 
 
 
Formal verification of eligibility criteria 
X 
 
 
 
 
 
 
 
Medical and disease history  
X 
 
 
 
 
 
 
 
Enrolment 
X 
 
 
 
 
 
 
 
Physical Exam 
 
 
 
 
 
 
 
Physical examination, Weight  
X 
 
 
 
 
 
 
 
WHO performance status 
X 
 
 
 
 
 
X 
 
Vital signs (temperature, respiratory rate, blood 
pressure, pulse) 
X 
 
 
 
 
 
 
 
Laboratory Exam 
 
 
 
 
 
 
 
Haematology and Serum chemistry (a) 
X 
 
 
 
X 
 
 
 
Tumor Biomarkers: CEA, CA 15-3 
X 
 
 
 
 
 
 
 
Pregnancy test (e) 
X 
 
 
 
 
 
 
 
Imaging 
 
 
 
 
 
 
 
FDG PET/CT scan with contrast agent injection 
X 
 
 
 
 
 
 
X (g) 
CT scan 
 
 
 
 
 
 
 
X(g) 
89Zr-Girentuximab PET/CT Imaging 
 
 
 
 
 
 
 
89Zr-Girentuximab administration 
 
X 
 
 
 
 
 
 
Whole body PET/CT imaging 
 
 
 
 
X 
 
 
 
Ancillary study : 89Zr-Girentuximab biodistribution 
 
 
 
 
 
 
 
89Zr-Girentuximab imaging Biodistribution (c) 
 
X 
X 
X 
X 
X 
 
 
89Zr-Girentuximab Blood pharmacokinetics (d) 
 
X 
X 
X 
X 
X 
 
 
Histological Analysis 
 
 
 
 
 
 
 
New or archival Tumor Histology  
X 
 
 
 
 
 
 
 
Safety 
 
 
 
 
 
 
 
Baseline findings / AE / SAE assessments 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
Antidrug Antibody HACA blood sample 
X 
 
 
 
 
 
 
X 
Vital signs (b) 
 
X 
 
 
 
 
 
 
 
(a) Blood count, creatinine clearance, glucose, bilirubin, ALAT, ASAT, Alkaline Phosphatases, Gamma GT. 
(b) Vital signs to be measured and monitored before 89Zr-Girentuximab administration and within 2 hours after 
administration (0,5 ; 1 and 2 hours) 
(c) 
whole body PET-CT imaging at D0 (dynamic imaging during 89Zr-Girentuximab administration), D1, D3 and D7 
(d) Pharmacokinetic blood samples to be taken before injection and at D0 after dynamic imaging, D1, D3, D5 and 
D7 
(e) A serum β-HCG pregnancy test will be performed only in premenopausal women at screening. Pregnancy test 
from urine (for premenopausal female patients) will be performed within 72 hours before 89Zr-Girentuximab 
administration   
(f) 
The Whole body PET/CT imaging could be done at D5 ± 2 
(g) CT scan or FDG PET/CT according to standard of care (with or without contrast agent injection) 
 
 

 
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TABLE OF CONTENTS 
 
PAGE 
 
PROTOCOL SYNOPSIS ______________________________________________________ 4 
ABBREVIATIONS AND DEFINITION OF TERMS __________________________________ 5 
HISTORY OF PROTOCOLE AMENDMENTS ______________________________________ 7 
TRIAL CALENDAR _________________________________________________________ 8 
SCHEDULE OF STUDY ASSESSMENTS __________________________________________ 9 
TABLE OF CONTENTS _____________________________________________________ 10 
1. 
INTRODUCTION ______________________________________________________ 14 
1.1 
Disease background ____________________________________________________ 14 
1.2 
Procedure background/non-clinical and clinical experience ____________________ 14 
1.3 
Rationale for conducting this study _______________________________________ 15 
1.4 
Benefit/risk and ethical assessment _______________________________________ 16 
1.4.1 
Individual benefit _____________________________________________________________ 16 
1.4.2 
Collective benefit _____________________________________________________________ 16 
1.4.3 
Overall risks _________________________________________________________________ 17 
1.4.4 
Benefit / risk balance __________________________________________________________ 17 
2. 
OBJECTIVES _________________________________________________________ 19 
2.1 
Primary objective(s) and endpoint ________________________________________ 19 
2.1.1 
Primary objective _____________________________________________________________ 19 
2.1.2 
Endpoints of primary objective __________________________________________________ 19 
2.2 
Secondary objective(s) and endpoint ______________________________________ 19 
2.2.1 
Secondary objectives __________________________________________________________ 19 
2.2.2 
Endpoints of secondary objectives _______________________________________________ 19 
2.3 
Exploratory objective(s) ________________________________________________ 20 
2.3.1 
Exploratory objectives _________________________________________________________ 20 
2.3.2 
Endpoints of Exploratory objectives ______________________________________________ 20 
3. 
STUDY DESIGN ______________________________________________________ 21 
3.1 
Overview of study design _______________________________________________ 21 
3.2 
Study design schedule __________________________________________________ 21 
3.3 
Study discontinuation __________________________________________________ 21 
4. 
PATIENT SELECTION __________________________________________________ 22 
4.1 
Population description _________________________________________________ 22 
4.2 
Inclusion criteria ______________________________________________________ 22 
4.3 
Non-inclusion criteria __________________________________________________ 22 

 
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4.4 
Withdrawal of patients from study _______________________________________ 23 
4.4.1 
Permanent discontinuation of procedure _________________________________________ 23 
4.4.2 
Withdrawal of consent ________________________________________________________ 23 
4.5 
Patients replacement __________________________________________________ 24 
5. 
STUDY PROCEDURE 89Zr-TLX250 PET/CT SCAN _____________________________ 25 
5.1 
Study drug 89Zr-TLX250 _________________________________________________ 25 
5.1.1 
Chemical Properties __________________________________________________________ 25 
5.1.2 
Pharmaceutical Properties _____________________________________________________ 25 
5.1.3 
Storage and Handling _________________________________________________________ 25 
5.1.4 
Packaging and Labelling _______________________________________________________ 26 
5.1.5 
Drug Logistics and Accountability ________________________________________________ 26 
5.2 
Study procedure: 89Zr-TLX250 PET/CT Imaging_______________________________ 27 
5.2.1 
Dosage and Administration _____________________________________________________ 27 
5.2.2 
89Zr-TLX250 PET/CT Imaging ____________________________________________________ 28 
5.2.3 
Imaging Analysis _____________________________________________________________ 28 
5.3 
Treatment Assignment _________________________________________________ 29 
5.4 
Blinding _____________________________________________________________ 29 
5.5 
Treatment Compliance _________________________________________________ 29 
5.6 
Radiation Precautions __________________________________________________ 29 
5.7 
Total Radiation Exposure _______________________________________________ 30 
5.8 
Prior and Concomitant therapy___________________________________________ 30 
5.8.1 
Permitted concomitant therapy _________________________________________________ 30 
5.8.2 
Prohibited concomitant therapy _________________________________________________ 31 
6. 
STUDY PROCEDURES: DESCRIPTION AND SCHEDULE ________________________ 32 
6.1 
Screening visit ________________________________________________________ 32 
6.2 
Enrolment ___________________________________________________________ 34 
6.3 
89Zr-TLX250 PET/CT Imaging _____________________________________________ 34 
6.3.1 
89Zr-TLX250 administration _____________________________________________________ 34 
6.3.2 
89Zr-TLX250 Imaging __________________________________________________________ 35 
6.4 
Follow-up visit: Day 30 following 89Zr-TLX250 PET scan ________________________ 35 
6.5 
End of study visit: 3 months (day 90) following 89Zr-TLX250 PET scan ____________ 35 
6.6 
Ancillary studies _______________________________________________________ 36 
6.6.1 
Ancillary Imaging study ________________________________________________________ 36 
6.6.2 
Ancillary Biological study _______________________________________________________ 36 
6.7 
Independent Central Histological analysis __________________________________ 36 
7. 
SAFETY _____________________________________________________________ 37 
7.1 
Definitions ___________________________________________________________ 37 
7.1.1 
Adverse event Definition _______________________________________________________ 37 
7.1.2 
Definition of serious adverse events _____________________________________________ 37 

 
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7.1.3 
Expected adverse events _______________________________________________________ 38 
7.1.4 
Unexpected adverse events ____________________________________________________ 38 
7.1.5 
New Safety Issue _____________________________________________________________ 38 
7.2 
Investigator obligations _________________________________________________ 38 
7.2.1 
Adverse Events reporting ______________________________________________________ 38 
7.2.2 
Serious Adverse Events (SAEs) Reporting __________________________________________ 39 
7.3 
Sponsor obligations ____________________________________________________ 41 
7.3.1 
SAE Analysis _________________________________________________________________ 41 
7.3.2 
Relationship Scoring __________________________________________________________ 41 
7.3.3 
Notification of SUSARs to competent authorities ___________________________________ 41 
7.3.4 
Notification of New Safety Issue _________________________________________________ 42 
7.3.5 
Reporting of DSURs (Development Safety Update Report) ____________________________ 42 
7.3.6 
Reporting of other safety data __________________________________________________ 42 
7.3.7 
In utero exposure ____________________________________________________________ 42 
8. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION _________________ 43 
8.1 
Brief reminder of study objectives ________________________________________ 43 
8.1.1 
Primary objective _____________________________________________________________ 43 
8.1.2 
Endpoints of primary objective __________________________________________________ 43 
8.1.3 
Secondary objectives __________________________________________________________ 43 
8.1.4 
Endpoints of secondary objectives _______________________________________________ 43 
8.1.5 
Exploratory objectives _________________________________________________________ 44 
8.1.6 
Endpoints of Exploratory objectives ______________________________________________ 44 
8.2 
Determination of sample size ____________________________________________ 44 
8.3 
Selection of patients to be included in the statistical analysis __________________ 44 
8.4 
Study feasibility _______________________________________________________ 44 
8.5 
Interim analyses ______________________________________________________ 44 
8.6 
Statistical criteria for study termination ___________________________________ 45 
8.7 
Handling of missing, unused or invalid data_________________________________ 45 
8.8 
Description of analysis sets ______________________________________________ 45 
8.8.1 
For Safety Analysis Set: ________________________________________________________ 45 
8.8.2 
For the determination of 89Zr-TLX250 PET-CT preliminary analysis of diagnostic performance:
 
45 
8.8.3 
For ancillary study set: ________________________________________________________ 46 
8.9 
Managing changes to the analysis sets _____________________________________ 46 
9. 
CONTROL AND QUALITY ASSURANCE ____________________________________ 47 
9.1 
Oversight Committees __________________________________________________ 47 
9.1.1 
Independent data monitoring committee _________________________________________ 47 
9.1.2 
Steering Executive Committee __________________________________________________ 47 
9.2 
Quality assurance _____________________________________________________ 47 
9.2.1 
Study monitoring _____________________________________________________________ 47 
9.2.2 
Monitoring Plan ______________________________________________________________ 48 

 
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9.2.3 
Inspection / Audits ___________________________________________________________ 49 
10. 
ETHICAL AND REGULATORY CONSIDERATIONS ___________________________ 50 
10.1 
Clinical trial authorisation _______________________________________________ 50 
10.2 
Patient Information and Consent _________________________________________ 50 
10.3 
Sponsor responsibilities ________________________________________________ 50 
10.4 
Investigator responsibilities _____________________________________________ 51 
10.5 
Human biological samples collection ______________________________________ 52 
10.6 
Patient Committees ____________________________________________________ 52 
11. 
COLLECTION AND MANAGEMENT OF RESEARCH DATA ____________________ 53 
11.1 
Collection of study data_________________________________________________ 53 
11.1.1 
Collection and conservation of study data _______________________________________ 53 
11.1.2 
Identification of all source data not contained in the patient medical file ______________ 53 
11.1.3 
Data coding _______________________________________________________________ 53 
11.2 
Study Data Processing __________________________________________________ 54 
11.2.1 
By the Sponsor ____________________________________________________________ 54 
11.2.2 
By sites, in the case of a computerised medical file is used _________________________ 54 
11.2.3 
Retention of documents _____________________________________________________ 55 
12. 
CONFIDENTIALITY AND OWNERSHIP OF DATA ___________________________ 56 
13. 
PUBLICATION AND VALORISATION RULES _______________________________ 57 
14. 
FINANCIAL ASPECTS ________________________________________________ 59 
15. 
LIST OF REFERENCES ________________________________________________ 60 
 
 
 
 

 
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The study sponsor, the Institut de Cancérologie de l’Ouest (ICO), declares that the "OPALESCENCE" 
clinical trial  will be conducted in accordance with the protocol, the French Public Health Code 
(articles 1121-1 et seq),  and the document Good Clinical Practice of November 24, 2006. 
 
1. 
INTRODUCTION 
 
1.1 
Disease background 
 
Triple-negative breast cancer (TNBC) is associated with a high risk of recurrence and generally a 
bad prognosis. More than one-third of patients with TNBC will present distant metastases during 
the course of their disease. Although chemotherapy has been the main treatment option for 
metastatic TNBC for a long time, this scenario has changed recently with the results of 
immunotherapy in patients with PD-L1-positive tumors. In patients with PD-L1-positive or negative 
tumors, a single agent chemotherapy metastatic first-line treatment regimen containing taxanes 
with or without bevacizumab could be used.   
 
The treatment of TNBC is constantly evolving.  To improve metastatic TNBC treatment outcomes, 
patients are encouraged to enroll in ongoing trials which are evaluating new targeted agents, 
immunotherapy and predictive biomarkers (1,2). 
 
Since Warburg introduced the so-called Warburg effect, characterized by unregulated glucose 
uptake and disruption of glycolytic metabolism in cancer cells, dysregulated energy metabolism has 
become known as an important part of the pathogenesis of uncontrolled growth in cancer cells (3). 
TNBC have generally been shown to have an exacerbated glycolytic metabolism when compared 
to non-TNBC (4,5).   
 
Recent insight on regulation of glycolysis suggests hypoxia-inducible factor 1-alpha (HIF1α) as a key 
regulator that enables tumor cells to survive by altering glucose metabolism (6). HIF1α is controlled 
by oxygen levels and is stabilized under hypoxic conditions. Stabilized HIF1α activates transcription 
of several genes implicated in glycolytic cancer metabolism, by increasing glucose transporter 
expression. This accelerates influx of glucose into tumor cells, and subsequent glycolysis results in 
tumor microenvironment acidosis (7). In order to overcome acidity, these microenvironmental 
stresses activate transcription of compensatory genes including the gene encoding carbonic 
anhydrase IX (CAIX), a member of metalloenzyme family that is a major downstream target of HIF1α 
(3,8,9).  
Based on these well characterized metabolic pathways in cancer cells and the tumor 
microenvironment, we propose to focus on the targeting of CAIX in TNBC. 
 
 
 
1.2 
Procedure background/non-clinical and clinical experience 
 
CAIX is normally expressed in intestinal and stomach mucosa, gallbladder and testis (10), but is 
upregulated in several forms of cancer, including breast cancer. Indeed, CAIX is a marker for hypoxic 

 
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regions of breast tumors (9,11) and is associated with poor prognosis (12–14) and high-grade, ER-
negative breast tumors (15). Its role in tumor growth and disease progression has been attributed 
to its ability to reduce pericellular pH in response to hypoxia (15–17), creating a toxic environment 
for normal cells (18). Acidic environments also facilitate the breakdown of the tumoral extracellular 
matrix (19) which can enhance metastatic activity (20,21).  
 
Several studies have identified altered HIF1α and CAIX protein expression levels to be related to 
poor prognosis in breast cancer (14,22–26). CAIX is expressed in 7 % of an unselected breast cancer 
cohort and in 25 % of TNBCs (27). CAIX expression rates increased with tumor grade (p < 0.001) and 
associations with tumor size were significant for CAIX (p < 0.001; positive association). Although 
based on only a few studies, CAIX showed profound lower expression rates in normal breast tissue 
and benign breast disease (p < 0.001), and high rates in carcinoma in situ (28). The expression levels 
of HIF1α and CAIX vary depending on the intrinsic subtype, and they are increased in TNBC 
compared to other subtypes (22). 
 
Three studies have investigated HIF1α and glucose metabolism for alternative therapeutic options 
to overcome breast cancer resistance to adjuvant therapeutic modalities (24,29,30). More recently, 
in early TNBC, combined HIF1α and CAIX protein expression may serve as an unfavorable prognostic 
indicator, particularly in patients receiving a cyclophosphamide-based chemotherapy or 
radiotherapy as well as those with basal phenotype of breast cancer (31).  
 
CAIX has recently emerged as a very attractive therapeutic target due to the following features:  
 
1. CAIX shows a tissue-restricted pattern and low expression levels in normal tissues, while it 
is induced in a broad range of cancers (32);  
 
2. It is located on the surface of cells (33);  
 
3. Its overexpression in cancers confers a survival advantage in hypoxia and facilitates cell 
migration and metastasis (34).  
 
Depletion of CAIX in cancer cell lines has been shown to attenuate the growth of tumor xenografts 
and inhibit the formation of spontaneous metastasis (35). Interestingly, CAIX was found to 
contribute to cell migration and invasion by facilitating formation of focal adhesions, ion-transport 
and pH control at the leading edge of lamellipodia of moving cells (36). Currently, substantial effort 
is devoted to the development of potent, cancer-selective CAIX inhibitors, including monoclonal 
antibodies (37). Moreover, recently, Chafe et al., suggested that targeting CAIX in the tumor 
microenvironment in combination with immune-checkpoint blockade is a potential therapeutic 
strategy for enhancing response and survival in patients with hypoxic solid malignancies (38). 
Another team developed a CAIX-targeted, human serum albumin (HSA) drug delivery vehicle which 
contained the potent anticancer drug, Paclitaxel (PTX). They used Acetazolamide (ATZ), a small 
molecule ligand of CAIX to selectively deliver HSA-PTX to TNBC cells (39). 
 
1.3 
Rationale for conducting this study 
 
Metastatic TNBC, due to its lack of usual BC target expression, its poor prognosis and the expression 
of CAIX in 25% of cases, seems to be an interesting clinical indication for studying CAIX targeting 

 
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using a radiolabeled a monoclonal antibody that recognizes carbonic anhydrase IX (89Zr-
Girentuximab or otherwise known as 89Zr-TLX250). 
  
89Zr-Girentuximab is under clinical development as a PET/CT imaging tracer for the detection of 
renal tumor masses and metastases (which overexpress CAIX). When the anti-CAIX antibody, 
girentuximab is labelled with a PET radionuclide such as 89Zirconium, it can be used as an imaging 
probe for PET. After intravenous administration of this imaging agent, the tumor, lymph nodes and 
distant metastases can be non-invasively assessed using whole-body PET imaging.  There is 
extensive clinical evidence demonstrating the ability of girentuximab-radiolabeled with PET 
radionuclides (Immuno-PET) to target CAIX lesions in patients with different type of solid tumors 
(37,40–42) 
 
While there is a lack of expression of common BC targets in TNBC, it is well known that 25% of 
TNBCs express CAIX, therefore there is a strong rationale for using a radiolabeled CAIX-targeting 
monoclonal antibody to detect and image TNBCs.  At present, FDG PET is routinely used to image 
breast cancer and we propose to compare the detection sensitivity of 89Zr-Girentuximab with FDG 
PET. In addition, we would like to assess the biodistribution and dosimetry of the 
radiopharmaceutical in metastatic TNBC patients with the objective of defining any possible future 
theranostic applications. 
 
1.4 
Benefit/risk and ethical assessment 
 
1.4.1 
Individual benefit 
 
There is no individual benefit to the patients included in the study. 
 
1.4.2 
Collective benefit 
 
It is therefore important to identify specific molecular targets that can be used for targeted cancer 
therapy, thereby limiting the progression and metastasis of this invasive tumor and improving 
patient outcomes. 
Although a challenge, the development of a targeted therapy for the treatment of TNBC is greatly 
needed and as it is essential that these patients gain access improved treatment regimens. 
CAIX, a cell surface antigen expressed in TNBC with a low expression level in normal tissues seems, 
thereby highlighting its potential value as a therapeutic target.  girentuximab is a monoclonal 
antibody that recognizes CAIX. The extensive clinical experience with radiolabeled girentuximab 
has provided strong clinical evidence to support its use as a targeted PET imaging agent. 
The initial objective of this study is to evaluate the biodistribution of 89Zr-girentuximab using PET-
CT (immuno-PET) imaging, which will allow us to show that CAIX could be a promising target and 
that the immuno-PET imaging tracer could act as an effective companion imaging diagnostic when 
screening patients for future therapies.  

 
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A secondary objective, is to provide preliminary clinical data that after screening patients with CAIX 
immuno-PET, the girentuximab has the potential to be radiolabeled with a therapeutic radionuclide 
such as Lutetium-177 (177Lu) to treat TNBC metastases in future clinical trials.  
 
1.4.3 
Overall risks 
 
In previous clinical studies, administration of Zirconium-89 (89Zr) labeled monoclonal antibodies 
was proven to be safe. 
Although never observed in previous trials, allergic-type reactions are possible during and 
immediately following the administration of girentuximab. In a total of more than 2000 
administrations of radiolabeled murine and chimeric girentuximab to humans, no allergic-type 
reaction was observed. 
In clinical studies administration of  (89Zr) labelled monoclonal antibodies were proven to be safe 
(40,43). 
Patients will be carefully monitored after 89Zr-Girentuximab administration. 
 
1.4.4 
Benefit / risk balance 
 
There is more than 20 years of experience in humans with SPECT/CT imaging using girentuximab 
labelled with various radioligands including 124I and 111In. These studies investigated the 
pharmacokinetics, toxicity, immunogenicity, and imaging characteristics of radiolabelled 
girentuximab in kidney cancer patients. 
 
In a clinical phase 1 study investigating safety, tolerability, imaging characteristics, biodistribution 
and dosimetry, 89Zr-TLX250 was found to be safe, and to provide improved imaging characteristics, 
compared to 124I-girentuximab, in line with preclinical findings (44). The clinical development of 
89Zr-Girentuximab has found the optimal dose of radioactivity to 37 MBq ± 10% of 89Zr with a total 
dose of girentuximab of 10 mg. 
 
Preliminary safety data in the ZIRDOSE study using 89Zr-girentuximab, administered 89Zr-TLX250 to 
5 patients at 5 mg and 10 mg girentuximab mass dose, each, did not prompt any safety concern. In 
the course of the study, no treatment-related SAEs or SUSARs were reported from any of the 10 
patients. A total of 7 AEs were experienced in 4 patients. An unlikely AE or no relationship to 
treatment was assessed by the investigator for 6 AEs. Mild nausea in one patient was considered 
by the investigator as possibly related to the study treatment. 
 
In previous 89Zr-TLX250 clinical studies, all patients had a whole body PET/CT scan. The CT scans 
were a low-dose CT for the purpose of attenuation correction of the PET data. Because acquisition 
parameters for the low-dose CT were restricted, the radiation dose from the low-dose CT was 
approx. 3 mSv. 
 
Radiation dosimetry was evaluated in a bridging dosimetry study (ZIRDOSE study) investigating the 
safety and tolerability of 89Zr-girentuximab. The whole body effective dose for administration of 
89Zr-girentuximab in this phase 1 study was 0.487 ± 0.014 mSv/MBq using the most widely 

 
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established dose calculation tool OLINDA 1.1 and the ICRP 60 standard (45). The absorbed/effective 
dose was calculated accordingly and resulted in a total whole body effective dose of 18.0 ± 0.5 mSv 
for 37 MBq. When a newer software IDAC-Dose 2.1 and the ICRP 103 standard (46) is used, the 
resulting effective dose will be 0.551 ± 0.030 mSv/MBq or 20.5 ± 1.1 mSv for 37 MBq. 
 
The combined whole body effective dose of 89Zr-girentuximab administration and low-dose CT is 
expected to be below 20 mSv based on the accepted standard OLINDA 1.1 and ICRP 60, or below 
23 mSv based on IDAC-Dose 2.1 and ICRP 103, for all patients. The lifetime attributable risk for 
incidence of radiation-induced cancer for an effective dose of 23 mSv is 0.4% (ICRP 103, 2007), 
which is comparable to the risk from a diagnostic CT of chest, abdomen and pelvis (47). 
 
Given the well-known safety and tolerability of radiolabelled girentuximab, confirmed for 89Zr- 
TLX250 in the context of a phase I safety study, and further considering the low antibody doses 
used in this study, no harmful effects exceeding the risk of established diagnostic imaging 
procedures are to be expected. The results of this study may contribute to the development of a 
new targeted therapy for TNBC, it appears that the benefit/risk ratio will be clearly in favour of the 
benefit to the patient. Indeed, if the imaging can clinically substantiate a potential new imaging and 
therapeutic target, this imaging agent could become a "companion imaging diagnostic" used to 
screen patients that have a higher likelihood of responding to a CAIX-targeted therapeutic 
radiolabeleld with 177Lu. Although, highly unlikely, 89Zr-TLX250 may cause allergic-type reactions. 
The study sites are well equipped to treat allergic/anaphylactic reactions. 
 
 

 
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2. 
OBJECTIVES 
 
2.1 
Primary objective(s) and endpoint 
 
2.1.1 
Primary objective 
 
To assess the concordance for tumor lesion detection using 89Zr-TLX250 PET/CT versus a 
conventional 18FDG PET/CT scan where comparison will be made on a per lesion analysis basis. 
 
2.1.2 
Endpoints of primary objective 
 
Concordance study of metastatic uptake seen in 18FDG PET/CT scan and 89Zr-TLX250 PET/CT scan 
per "lesion" by comparing for each lesion the CT scan, 18FDG PET scan and 89Zr-TLX250 PET/CT scan 
by assessing a ratio "Number of positive or negative 89Zr-TLX250 lesions / Number of positive or 
negative FDG lesions” and "Number of positive or negative 89Zr-TLX250 lesions / Number of CT scan 
lesions”. 
 
2.2 
Secondary objective(s) and endpoint 
 
2.2.1 
Secondary objectives 
 
1. To determine the percent of total tumor burden (whole body) detected on 89Zr-TLX250 
PET/CT scan compared to that defined on 18FDG PET/CT used as the reference. 
2. To assess the correlation between the normalized uptake values (SUV) of 89Zr-TLX250 
and CAIX histological expression if a biopsy is done. 
3. To confirm the perfect safety and tolerability of 89Zr-TLX250 and assess the generation 
of human anti-chimeric antibodies in response to the girentuximab. 
 
2.2.2 
Endpoints of secondary objectives 
 
1. Percent of positive CA IX metastatic tumor burden compared to total metastatic tumor 
burden by 18FDG (ratio "Number of positive 89Zr-TLX250 lesions / Number of positive 
FDG lesions") 
2. If a metastasis biopsy is conducted, assessment of the correlation between the 
normalized uptake values (SUV) of 89Zr-TLX250 positive lesions and CAIX histological 
expression will be done by comparing the 89Zr-TLX250 semi-quantitative data with the 
immunohistochemical results (IHC) of biopsied metastases. 
3. The safety and tolerability of 89Zr-TLX250 will be evaluated by measuring and 
monitoring vital signs within 2 hours after injection of the radiopharmaceutical. The 
patient will be informed that in the event of abnormal physical signs, occurring within 
24 hours after 89Zr-TLX250 administration, he must report them to the investigator for 

 
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registration. The reporting period of AEs (related to 89Zr-TLX250) and SAEs cover a 
period of 30 days after 89Zr-TLX250 administration. 
 The NCI Common Toxicity Criteria, version 5.0 reference will be used. 
 HACA (Human anti-chimeric antibody) will be assessed. 
 
2.3 
Exploratory objective(s)  
 
2.3.1 
Exploratory objectives 
 
For 3 to 5 patients, assessment of the absorbed doses received by organ and in whole body after 
89Zr-TLX250 administration for imaging purpose in metastatic TNBC patients. 
 
 
2.3.2 
Endpoints of Exploratory objectives 
 
 
For 3 to 5 patients, quantitative biodistribution of 89Zr-TLX250 will be evaluated from sequential 
whole body PET-CT imaging and pharmacokinetic data (blood samples) taken at D0 (before and 
after 89Zr-TLX250 administration), D1, D3, D5 and D7. 
 
 
 
 
 

 
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3. 
STUDY DESIGN 
 
3.1 
Overview of study design 
 
The research presents the following characteristics: 
- 
feasibility study   
- 
Imaging Study 
- 
Pilot trial 
- 
Monocentric  
- 
Non randomized  
- 
Uncontrolled 
- 
Open-label 
- 
Prospective  
 
 
3.2 
Study design schedule 
 
 
Figure 1: Study design schedule 
 
 
3.3 
Study discontinuation  
 
The study could be interrupted or terminated by the sponsor in agreement with the coordinator and 
with the competent authorities for the following reason: 
- 
frequency and/or unexpected severity of the toxicity, 
- 
recruitment of patients too low, 
- 
poor quality of the data collected, 
 
 
 

 
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4. 
PATIENT SELECTION  
Each patient should meet all of the inclusion criteria and none of the non-inclusion criteria for this 
study. Under no circumstances can there be exceptions to this rule.  
If they meet the inclusion and non-inclusion criteria, patients will be offered the research after 
discussion with a nuclear physician in charge of the study. The latter will present the study as well as 
the benefits and risks of the trial procedure. The patient will be given the necessary reflection time 
before signing the consent form. 
 
4.1 
Population description 
 
Patients with Triple Negative Breast Cancer recurrence. 
 
4.2 
Inclusion criteria 
Patients must meet all of the following inclusion criteria to be eligible for enrolment into the study: 
 
1. Written informed consent obtained from the patient prior to performing any protocol-
related procedures, including screening evaluations.  
2. Female or male, Age ≥ 18 years at time of study entry. 
3. Primitive triple negative breast cancer proven histologically, defined according to the 
following criteria: 
 Estrogen receptors <10%. 
 And progesterone receptors <10%. 
 And HER2 not amplified or not overexpressed. 
4. Metastatic Breast Cancer documented by conventional imaging and/or FDG PET/CT with at 
least one measurable metastatic lesion according to RECIST and/or PERCIST. 
5. Consent to use a contraception method for at least 30 days after administration of 89Zr-
TLX250.  
6. ECOG Performance Status 0 or 1. 
7. Life expectancy at least 6 months. 
8. Patient has valid health insurance. 
9. Patient is willing and able to comply with the protocol for the duration of the study including 
undergoing treatment and scheduled visits and examinations including follow up. 
 
4.3 
Non-inclusion criteria 
Patients should not enter the study if any of the following non-inclusion criteria are fulfilled: 
 
1. History of another primary malignancy except for basal cell carcinoma within the last 5 
years. 
2. Chemotherapy, radiotherapy, or immunotherapy within 4 weeks prior to the planned 
administration of 89Zr-TLX250 or continuing adverse effects (> grade 1) from such therapy 
(Common Terminology Criteria for Adverse Events [CTCAE] version 5.0). 

 
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3. Planned antineoplastic therapies (for the period between IV administration of 89Zr-TLX250 
and imaging). 
4. Exposure to murine or chimeric antibodies within the last 5 years. 
5. Previous administration of any radionuclide within 10 half-lives of the same. 
6. Impossibility to hold lying motionless at least 1 hour, or known claustrophobia. 
7. Serious non-malignant disease (e.g. psychiatric, infectious, autoimmune or metabolic), that 
may interfere with the objectives of the study or with the safety or compliance of the 
subject, as judged by the investigator. 
8. Mental impairment that may compromise the ability to give informed consent and comply 
with the requirements of the study. 
9. Pregnant or likely to be pregnant or nursing patient. 
10. Known hypersensitivity to girentuximab or desferoxamine. 
11. Renal insufficiency with GFR ≤ 45 mL/min/ 1.73 m². 
12. Persons deprived of their liberty, under a measure of safeguard of justice, under guardianship 
or placed under the authority of a guardian. 
13. Disorder precluding understanding of trial information or informed consent. 
 
Participation to another interventional therapeutic clinical trial is not authorized. 
 
Procedures for withdrawal of incorrectly enrolled patients are presented in Section 4.4. 
If a patient withdraws from participation in the study, then his or her enrolment code cannot be 
reused.  
 
4.4 
Withdrawal of patients from study  
 
4.4.1 
Permanent discontinuation of procedure  
 
Patients may be discontinued from study in the following situations: 
• 
Patient decision. 
• 
Investigator decision. 
• 
Patient did not undergo 89Zr-TLX250 PET/CT imaging study procedure. 
 
4.4.2 
Withdrawal of consent 
 
Patients are free to withdraw from the study at any time (study procedure and assessments) without 
prejudice to their further medical care. 
In case of withdrawal of consent, the patient's study generated data may be used until withdrawal of 
consent date, unless the patient has objected.  
 

 
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4.5 
Patients replacement  
 
A patient who is included into the study, but then fulfils any one of the following, will be considered a 
drop-out: 
• 
Has not received IV 89Zr-TLX250; 
• 
Did not undergo 89Zr-TLX250 PET/CT imaging after IV administration of study drug; 
• 
Whose PET/CT images cannot be analysed due to technical failure; 
Patients who dropped out of the study will be replaced. All patients who dropped-out after receiving 
IV 89Zr-TLX250 will need to get all the examinations and blood draws as for the final study visit. 
 
 

 
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5. 
STUDY PROCEDURE 89Zr-TLX250 PET/CT SCAN 
 
5.1 
Study drug 89Zr-TLX250 
 
5.1.1 
Chemical Properties  
 
89Zr-TLX250, is a chimeric monoclonal antibody (INN name: Girentuximab) with specificity for the CAIX 
(carbonic anhydrase 9) antigen, radiolabelled with the positron emitting radio-metal zirconium-89. 
Girentuximab has a CAS number of 916138-87-9.  
The chemical formula, without the 89Zr, is C6460H1006N1718O2018S48 with a molecular mass of 146.5 
kg/mol. 
 
5.1.2 
Pharmaceutical Properties 
 
89Zr-TLX250 is formulated as a solution for intravenous administration in glass vials at the nominal 
dosage strength 37 MBq (±10%) for single intravenous use. The 89Zr-TLX250 drug product is 
manufactured as “ready-to-use”. The composition of 89Zr-TLX250 solution for IV administration 
includes the active pharmaceutical ingredient in a buffered solution without other excipients, as 
follows: 
 
Active component:  
37 MBq 89Zr-TLX250  
Batch volume:  
≤ 10 mL  
Mass dose girentuximab  
10 mg  
Other ingredients:  
Girentuximab, 89Zr-DFO-girentuximab  
Solvent:  
NaCl 0.9%  
Appearance:  
Clear, colourless to light yellow and free from 
visible particles  
pH:  
5.0 – 8.0  
Radiochemical purity: (ITLC after purification)  
89Zr-TLX250 ≥ 90%  
Radiochemical purity (SE-HPLC after 
purification)  
89Zr-DFO-girentuximab ≥ 90%  
89Zr / 89Zr-DFO ≤ 10%  
Aggregates ≤ 5%  
Identity:  
Rtsample = Rtreference ± 10%  
Sterility  
No growth  
Endotoxins  
≤ 17.5 EU/mL  
Expiry time  
96 hours at 15°C - 30°C in bulk vial  
Primary packaging  
Type 1 glass vials  
 
A complete record of batch numbers and expiry dates of all study medication will be maintained in 
the trial master file (TMF). 
5.1.3 
Storage and Handling 
The product is to be shipped and stored at room temperature (15°C to 30°C) inside the lead-shielded 
container provided and protected from light.  

 
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The product must be handled within a hospital environment only, by an accredited radiopharmacist 
and/or nuclear medicine physician according to international and local radiation protection guidelines. 
 
5.1.4 
Packaging and Labelling 
 
89Zr-TLX250 solution for IV administration will be supplied in glass vials in appropriate packaging (lead-
shielded containers bearing a radioactive warning symbol in accordance with radioactive 
pharmaceutical requirements). The labels of the packaging supplied by the sponsor will include the 
following information as a minimum:  
• 
Name and address of sponsor  
• 
Study number  
• 
Name of study drug and formulation  
• 
Dose strength  
• 
Batch number  
• 
Expiry date  
• 
Storage instructions  
• 
Radioactive warning symbol  
• 
“For Clinical Trial Use only”.  
 
All manufacturing, formulation and labelling will be done in accordance with applicable current GMP 
and local guidelines and laws. 
 
 
Medication Numbering: 
A system of medication numbering in accordance with all requirements of Good Manufacturing 
Practice (GMP) and any applicable regulatory requirement will be used for all study drugs. This will 
ensure that, for each patient, any dosing of study drug can be identified and traced back to the original 
bulk ware of the active ingredients.  
Lists linking all numbering levels will be maintained by the institutions in charge of study drug 
packaging. 
 
5.1.5 
Drug Logistics and Accountability  
 
5.1.5.1 
Supply, Storage, Dispensation and Return  
 
89Zr-TLX250 solution for IV administration will be manufactured, handled and stored in accordance 
with GMP. 89Zr-TLX250 contains radioactive material and should only be handled by personnel trained 
in the use of radioactive isotopes with proper shielding and monitoring. Receipt and use of 89Zr-TLX250 
is limited to institutions holding an appropriate handling permit by their competent national or 
regional authority. 
 
All required documentation, e.g. written approval from the independent ethics committee 
(IEC)/institutional review board (IRB) and regulatory authority, as appropriate, needs to be provided 
before ordering for a site can take place. The dose order will be a direct order from the study site to 
the Sponsor who shall arrange appropriate supply of IMP (please refer to the IMP Handling Manual 

 
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for details). Upon establishment of patient eligibility (see Section 4), the clinical site manager will order 
individualized doses of 89Zr-TLX250 solution for IV administration, via the Sponsor for direct delivery 
to the study site. A dose can be cancelled at any time however if the cancellation is less than 2 days 
prior to administration date then the site will need to follow IMP handling manual for appropriate 
disposal of product. 89Zr-TLX250 for IV administration will be provided by Telix International Pty Ltd 
and used unchanged from the original state. The treating investigator at the site will delegate ordering 
of 89Zr-TLX250 solution for IV administration to the clinical site manager, overseeing eligibility and 
planned treatment dates, for direct delivery to the site to the attention of the radiopharmacist.  
The IMP will be shipped at room temperature (15°C to 30°C) inside an appropriately shielded 
container.  
Upon receipt at site, 89Zr-TLX250 solution for IV administration will be kept in a secure, temperature-
controlled, restricted-access location and in accordance with applicable regulatory requirements at 
the radiopharmacy of the site. The IMP should be stored at ambient temperature (15°C to 30°C) 
without freezing, and should be used by the expiration date and time printed on the label. 
 
89Zr-TLX250 doses will be accompanied by an individual certificate of analysis for each batch. Upon 
verification of the correct radioactive dose, as specified by the study protocol, the radiopharmacist 
will hand over the investigational product in a syringe, kept in a lead-shielded container, to the nuclear 
medicine investigator, or a designated and suitably qualified deputy for administration. This syringe 
will be labelled by the radiopharmacist according to institutional standards.  
Storage, handling and destruction must be performed according to local guidelines regarding 
radioactive waste management. Details are outlined in the IMP Handling Manual. 
 
5.1.5.2 
Drug Accountability  
 
The radiopharmacist will confirm receipt of the study drug by e-mail or the method given in the IMP 
Handling Manual and will use the study drug only within the scope of this clinical study and in 
accordance with this study protocol. He / she will keep a record of the dispensed study drug.  
Receipt, distribution and return of the study drug must be properly documented on the forms 
provided by the sponsor giving the following information: study protocol number, sender, receiver, 
date, mode of transport, quantity, batch number, expiration date and retest date, if applicable. 
The sponsor will monitor the drug accountability records at regular points during the study and will 
perform drug reconciliation at the end of the study. 
 
5.2 
Study procedure: 89Zr-TLX250 PET/CT Imaging 
All imaging sequences are done on an outpatient basis. The patient does not have to be fasting. There 
is no premedication or other treatment before and after the 89Zr-TLX250 administration. 
 
5.2.1 
Dosage and Administration 
The mass dose of 89Zr-TLX250 to be used in this study will be 10 mg, labelled with 37 MBq (±10%) 89Zr 
per dose.  
 

 
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Each patient will receive a single slow intravenous (IV) administration over a minimum of 3 minutes 
on Day 0 (after pre-dose assessments), at the nuclear medicine service of the respective study site.  
No dietary constrictions prior to dosing are necessary.  
Prior to administration, an indwelling intravenous catheter has to be placed into the antecubital vein 
or an equivalent venous access. The radiopharmaceutical will be slowly administered through the 
indwelling catheter and followed with a saline flush. The syringe will be assayed prior and after 
administration to assess injected radioactive dose (MBq).  
The dose that will be administered to the individual patient will be assessed using a dosing calibrator 
as outlined in the IMP Handling Manual. 
 
5.2.2 
89Zr-TLX250 PET/CT Imaging  
 
On D5 (± 2) days post administration of 89Zr-TLX250, a whole body PET/CT scan will be acquired from 
skull to mid-thigh using 6-8 bed positions with 10 minute acquisition time per bed position. 
 
Ancillary imaging study:  
 
For 5 patients, imaging quantitative biodistribution of 89Zr-TLX250 will be evaluated from sequential 
whole body PET-CT imaging and pharmacokinetic blood samples at D0, D1, D3, D5 and D7 (see section 
6.6). 
 
5.2.3 
Imaging Analysis 
 
5.2.3.1 
Qualitative 89Zr-TLX250 Tumor Targeting 
 
89Zr-TLX250 tumor uptake will qualitatively be assessed, considering whether or not 89Zr-TLX250 
binding the target lesions determined on FDG PET-CT as metastatic lesions. 
The interpretation of the 89Zr-TLX250 PET/CT images as positive or negative for metastatic TNBC will 
be made on the basis of visual examination only. 
The 89Zr-TLX250 PET/CT images will be evaluated for evidence of radioactive uptake in the metastatic 
TNBC lesions. The local and central reviewers will designate the lesions as having a status of positive 
or negative. 
The 89Zr-girentuximab PET/CTs will be assessed in a central reviewing system to ensure true lesion 
detection and reproducible inter-observer agreement. All 89Zr-girentuximab PET/CTs would be 
assessed by two expert nuclear physicians independently.  
The first evaluation will be done by the nuclear physician, in charge of the patient during the 89Zr- 
girentuximab PET/CT exam. 
The second evaluation will be done by a second nuclear physician who should be blinded for  
evaluation of the first nuclear physician. However, for patient safety reasons, the nuclear physician 
should be allowed to communicate findings that required (local) interventions (e.g. brain metastases). 
The two reports would be harmonized to one final report by the first  reviewer. In case of different 
findings, a third nuclear physician should  evaluate the 89Zr- girentuximab PET/CT exam to reach a 
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A tumor lesion will be defined visually positive based on anatomical substrate on low-dose CT in 
combination with 18FDG and/or 89Zr-girentuximab-uptake.Quantification of positive lesions as defined 
by evaluation reports for 18FDG and 89Zr-girentuximab PET/CT will be performed by drawing regions-
of-interest using dosisoft (PLANET Edition 3 – PLANET Onco Dose, Version 3.1.1.50 – 2021-01-03).  
The maximum and mean standardized uptake values (SUV) will be calculated. SUVmax will be used for 
tumor tracer-uptake; SUVmean for measuring uptake in healthy organs and blood pool. 
 
The lesion will be classified as PET-positive if: 
• 
Radioactivity in the lesion is clearly visible (as described above), AND 
• 
With a same location as FDG positive lesions described previously. 
5.2.3.2 
Semiquantitative 89Zr-TLX250 Tumor Targeting 
 
SUVs will be calculated for each tumor lesion, considering the measured tumor-bound activity, the 
injected activity dose, and the body weight and height of each patient. SUV values will be compared 
with the degree of CAIX expression determined by immunohistochemistry, using a 5-point scale. 
 
5.3 
Treatment Assignment  
 
Once full establishment of eligibility by the site, the physician will confirm patient eligibility, the 
patient number will be allocated and 89Zr-TLX250 imaging should be scheduled before the 
administration of the study drug.  
Then, the authorized site representative for the study can order the study drug through the “89Zr-
TLX250 Order Form”.  
 
5.4 
Blinding  
Not applicable, this is an open-label study.  
 
5.5 
Treatment Compliance  
 
89Zr-TLX250 will be administered by study personnel at the site. Details of each administration will be 
recorded in the eCRF. 
  
5.6 
Radiation Precautions  
Medical administration of radioactive diagnostic tracers such as 89Zr-TLX250 is guided by national 
radiation safety regulations, differing extensively between countries.  
Excretion limits acceptable for discharge will be defined by the investigators in compliance with the 
local regulations. Commonly, patients will be discharged from the hospital 2 hours p.a., unless the 
investigator decides otherwise. 

 
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Patients will be encouraged to increase fluid intake and to void frequently through the first day after 
administration.  
The following safety precautions apply for patients:  
• 
Patients should be advised to observe rigorous hygiene in order to avoid risk of contamination 
of others using the same toilet facility.  
• 
A double toilet flush is recommended.  
• 
Patients should wash their hands thoroughly every time after using the toilet.  
• 
During the first week after treatment, patients should follow detailed instructions, as given in 
the trial informed consent form, regarding their distance from and contact to other persons 
(especially pregnant women and children)..  
 
The following precautions apply for health care workers and for laboratory assessments:  
Healthcare personnel are advised to limit the time of close contact with patients injected with (89Zr)-
labelled radiopharmaceuticals. Use appropriate shielding on the day of administration. Laboratory 
assessments will be performed by the central laboratory. Because of the potential for radioactivity in 
some blood and urine samples, the site personnel must adhere to their SOPs and/or any guidance and 
regulations for handling radioactive substances. It is mandatory to use protective high quality 
(latex/nitrile) gloves in any direct contact with the radiopharmaceutical (vial/syringe) and with the 
patient.  
 
5.7 
Total Radiation Exposure 
 
Radiation dosimetry was evaluated in a bridging dosimetry study (ZIRDOSE study) investigating the 
safety and tolerability of 89Zr-girentuximab. The whole body effective dose for administration of 89Zr-
girentuximab in this phase 1 study was 0.487 ± 0.014 mSv/MBq using the most widely established 
dose calculation tool OLINDA 1.1 and the ICRP 60 standard (45). The absorbed/effective dose was 
calculated accordingly and resulted in a total whole body effective dose of 18.0 ± 0.5 mSv for 37 MBq. 
When a newer software IDAC-Dose 2.1 and the ICRP 103 standard (46) is used, the resulting effective 
dose will be 0.551 ± 0.030 mSv/MBq or 20.5 ± 1.1 mSv for 37 MBq. 
 
5.8 
Prior and Concomitant therapy 
 
At baseline screening, all prior cancer-related treatments are to be recorded. 
All other medications taken within 30 days before 89Zr- Girentuximab PET/CT exam, and any 
medications prescribed for chronic or intermittent use during the study or dose adjustments of these 
medications must be recorded on the case report form. 
 
 
5.8.1 
Permitted concomitant therapy 
 
Not applicable. 
 

 
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5.8.2 
Prohibited concomitant therapy 
 
Not applicable. 
 
 
 

 
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6. 
STUDY PROCEDURES: DESCRIPTION AND SCHEDULE 
 
Before study entry, throughout the study, and following study drug discontinuation, various clinical 
and diagnostic laboratory evaluations are outlined. The purpose of obtaining these detailed 
measurements is to ensure adequate safety and tolerability assessments. Clinical evaluations and 
laboratory studies may be repeated more frequently if clinically indicated. The Schedules of 
Assessments during the screening and treatment period is provided following the Protocol. 
 
6.1 
Screening visit 
 
Screening procedures will be performed up to 30 days before 89Zr- Girentuximab PET/CT exam. All 
patients must first read, understand, and sign the ICF. 
No trial-related procedures will be initiated before the signed consent has been obtained.  
After signing the ICF, completing all screening procedures, and all eligibility criteria confirmed, patient 
will be enrolled in the study.  
All procedures performed prior to the signing of the ICF and considered as standard of care may be 
used as screening assessments if they are performed within the 30 days prior to 89Zr-TLX250 PET scan. 
Except for radiological assessments which could be done within 6 weeks prior to 89Zr-TLX250 PET scan 
and Tumor Biomarkers within 3 months prior to 89Zr-TLX250 PET scan). 
 
The following procedures will be performed during the Screening Visit: 
• 
Informed Consent 
• 
Subject registration and subject number assignment 
• 
Review of eligibility criteria and confirm eligibility 
• 
Demographics 
• 
Record Medical History  
• 
Record Disease History: Biopsy and surgery histopathological reports 
• 
Record Breast Cancer-related treatment 
• 
Perform full physical examination with ECOG Performance Status and Vital signs  
• 
Review of prior/concomitant medications  
• 
Imaging exams:  18FDG PET/CT scan with contrast agent injection (Within 6 weeks prior to 89Zr-
TLX250 PET/CT scan)  
• 
Tumor Biomarkers: ACE, CA 15-3 (within 3 months prior to 89Zr-TLX250. 
• 
Standard laboratory samples for Haematology and serum Chemistry. 
• 
Serum β-HCG pregnancy test in women of childbearing potential and Urine Pregnancy test 
within 72 hours before 89Zr-TLX250 PET/CT scan.  
• 
Blood draw for HACA testing. 
 
 
• Medical history  
Breast Cancer Disease history will be reported, including date of diagnosis, histological results and 
previous Breast cancer treatments. 

 
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Relevant findings from medical history (obtained at screening) and physical examination will be 
reported. 
Relevant concomitant medications will be reported. 
 
• Physical examination and vital signs 
A complete physical examination will be performed within 30 days before patient enrolment. 
The performance status will be assessed. 
Vital signs (blood pressure [BP], pulse, temperature, and respiration rate) will be evaluated according 
to the assessment schedules Body weight and height. 
 
• Imaging assessments 
18FDG PET/CT scan with contrast agent injection should be performed within 30 days prior to 89Zr-
TLX250 PET/CT scan. 
18FDG-PET/CT scans are performed according to standard clinical practice by an experienced local 
nuclear physician. 
 
• Laboratory evaluations 
Clinical laboratory analyses (Haematology: blood count, and Chemistry: Creatinine clearance, fasting 
Glucose, Bilirubin, ALAT, ASAT, Alkaline Phosphatases, Gamma GT) are to be performed by the local 
laboratory within 30 days prior to 89Zr-TLX250 PET/CT scan. 
Tumor Biomarkers: CEA, CA 15-3 will be performed (accepted if done within 3 months prior to 89Zr-
TLX250). 
All female patients of childbearing potential (premenopausal women) must undergo a serum β-HCG 
pregnancy test at screening.  
Pregnancy test from urine must be performed (for patients of childbearing potential) within 72 hours 
before 89Zr-TLX250 PET/CT scan.  
 
• Immunogenicity evaluation 
A blood sample will be drawn in order to evaluate the immunogenicity (possible formation of 
antibodies) against the Girentuximab antibody (human anti-chimeric antibodies, HACA). 
 
An approximately 4 mL blood sample will be collected, before 89Zr-TLX250 administration, in an  red 
top SST tube, clotted 30 minutes (max.60 min) and centrifuged, within 1 hour of collection, at 1800 g  
for 10-15 minutes. Three serum aliquots will be transferred into three separately labelled 2 mL cryo-
vial and stored at –20°C. Please refer to the central laboratory manual for details on shipping.  
The presence of HACA in sera of patients will be tested quantitatively and qualitatively using validated 
ELISAs in the Bioanalytics Department of Agilex Biolabs Pty Ltd, South Australia, Australia. 
 
Instructions for collection, preparation and shipment can be found in the laboratory manual. Required 
sample collection information must be entered on the appropriate eCRF pages and requisition forms. 
 

 
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6.2 
Enrolment   
Patient Enrolment may occur only after the completion of the screening evaluations and confirmation 
of subject eligibility. 
Enrolment will be centralized and performed via the eCRF. 
How to connect to the eCRF: 
- Go to website: 
https://www.cancero-go-online.org/CSOnline/ 
- Study code: 
CRGA0065  
- Study Sponsor number : 
ICO-2020-25 
- Username and password: 
Nominative and personal, they will be given to each 
participant after investigation site participation setup visit 
opening of the site. 
 
 
If the software is unavailable, the enrolment registration request will be centralized at the sponsor 
ICO “Service Promotion de la Recherche Clinique”. A registration Form is provided for this purpose. 
It will be sent by e-mail to the sponsor (between 9am and 5pm). An enrolment number will be assigned 
to the patient and e-mailed to the site. 
 
Sponsor Contact Information :  DRC de l’ICO / Cellule de Promotion 
Tél. : +33 (0)2 40 67 98 26 
Chef de Projet : Nadia ALLAM 
E-mail : promotionrc@ico.unicancer.fr 
 
After the enrolment procedure is completed, the investigator will receive by email a confirmation of 
the patient enrolment, the centre identification number, the patient identification number.  
 
After the enrolment, each patient will receive a “patient card” (Appendix 6) specifying the procedure 
received in the trial. The patient may present this card to any health professional encountered during 
the trial. 
 
6.3 
89Zr-TLX250 PET/CT Imaging 
 
6.3.1 
89Zr-TLX250 administration 
 
The following examinations and procedures will be performed on Day 0 before 89Zr-TLX250 
administration: 
• 
Physical exam. 
• 
Pre-dose Vital signs. 
• 
Pregnancy test from urine (for female patients of childbearing potential) within 72 hours 
before 89Zr-TLX250 administration. 

 
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• 
Baseline findings. 
• 
Concomitant medication. 
 
Administration of 89Zr-TLX250 will be slowly conducted over a minimum of 3 minutes via the IV route 
(see Section 5.2.1). The intravenous line should be flushed slowly with normal saline and the end of 
administration time recorded.  
The dose syringe should be assayed for residual radioactivity and the net activity administered to the 
patient recorded.  
Vital signs will be assessed immediately after the slow injection of 89Zr-TLX250 dose, 30 minutes, 1 
hour and 2 hours after 89Zr-TLX250 administration. 
Adverse event monitoring will be assessed within 2 hours post administration. 
If adverse events occur within 30 days post administration, the patient must inform the investigator. 
These adverse events will be reported in the e-CRF.  
 
6.3.2 
89Zr-TLX250 Imaging 
 
On D5 ± 2 days post administration of 89Zr-TLX250, a whole body PET/CT imaging will be performed 
from skull to mid-thigh using 6-8 bed positions with 10 minute acquisition time per bed position. 
Laboratory assessments will be performed: Blood count, creatinine clearance, glucose, bilirubin, ALAT, 
ASAT, Alkaline Phosphatases, and Gamma GT. 
 
6.4 
Follow-up visit: Day 30 following 89Zr-TLX250 PET scan 
 
30 days after 89Zr-TLX250 PET scan, a visit by the investigator will be performed to assess: 
• 
Performance Status (WHO) 
• 
The clinical status of the patient and review of AE and SAE. 
 
 
6.5 
End of study visit: 3 months (day 90) following 89Zr-TLX250 PET 
scan 
 
End of study visit will be performed 3 months after 89Zr-TLX250 PET / CT scan. 
All required procedures may be completed within 3 months ± 15 days of the end of study visit.  
• 
Complete physical exam  
• 
Evaluation of Performance Status (WHO) 
• 
Review of AE and SAE + prior/concomitant medications 
• 
Blood draw for HACA testing.  
• 
Imaging exams:  CT scan or 18FDG PET/CT scan with or without contrast agent injection. 
 

 
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6.6 
Ancillary studies 
The ancillary imaging and biological studies are optional. All patients enrolled in this trial will be asked 
to consent to these ancillary studies. 
 
6.6.1 
Ancillary Imaging study 
For 3 to 5 patients, imaging quantitative biodistribution of 89Zr-TLX250 will be evaluated from 
sequential whole body PET-CT imaging at: 
• 
D0, dynamic data acquisition during 89Zr-TLX250 administration. 
• 
D1 after 89Zr-TLX250 administration. 
• 
D3 after 89Zr-TLX250 administration. 
• 
D5 after 89Zr-TLX250 administration. 
• 
D7 after 89Zr-TLX250 administration. 
  
 
6.6.2 
Ancillary Biological study 
For these 3 to 5 patients, quantitative biodistribution of 89Zr-TLX250 will be evaluated in serum. 
Blood samples (one heparin tube : 4 ml) will be drawn at: 
 
• 
D0 before 89Zr-TLX250 administration. 
• 
D0, after dynamic acquisition, after 89Zr-TLX250 administration. 
• 
D1 after 89Zr-TLX250 administration. 
• 
D3 after 89Zr-TLX250 administration. 
• 
D5 after 89Zr-TLX250 administration. 
• 
D7 after 89Zr-TLX250 administration. 
 
Each blood sample will be analyzed for serum 89Zr radioactivity levels in the local nuclear medicine 
department.  
 
6.7 
Independent Central Histological analysis 
 
An independent central histology analysis will be carried out at ICO Saint Herblain. The purpose of 
this analysis is the determination of the degree of CAIX expression from the biopsy tumor sample. 
The degree of CAIX expression will be investigated and classified. 
 
 

 
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7. 
SAFETY 
ICH requires that both investigators and sponsor follow specific procedures when notifying and reporting 
adverse events/reactions in clinical trials. These procedures are described in this section of the protocol. 
 
7.1 
Definitions 
7.1.1 
Adverse event Definition  
 
An adverse event (AE) is defined as any untoward medical occurrence, in a patient or clinical trial subject treated 
by a medicinal product and which does not necessarily have a causal relationship with this treatment. 
Intensity (severity): 
  
Intensity of adverse events is assessed by the investigator. The intensity criterion should not be 
confused with the seriousness criterion, which is the guide for defining the reporting requirements. 
 
The intensity of adverse events will be classified according to the NCI-CTCAE Version 5.0.  
For any event not listed in this classification, the classification will be assessed as follows:  
• 
Mild (grade 1): does not affect the patient's Activities of Daily Living (ADL) 
• 
Moderate (grade 2): disrupts the patient's ADL 
• 
Severe (grade 3): disabling; limiting self-care ADL 
• 
Life-threatening (grade 4): urgent intervention indicated. 
• 
Death (Grade 5) 
 
Causal relationship to study drug/procedure: 
 
Relationship between the AE and the study drug /procedure must be assessed following EVCTM 
(EudraVigilance Clinical Trial Module) criteria: reasonable possibility / no reasonable possibility. 
Important factors to be considered in assessing the relationship of the AE to study treatment include: 
• 
The temporal sequence from drug/procedure administration 
• 
Recovery on drug discontinuation (de-challenge), recurrence on drug re-introduction (re-
challenge). 
• 
Underlying, concomitant, intercurrent diseases. 
 
 
 
 
 
7.1.2 
Definition of serious adverse events 
A serious adverse event (SAE) is an AE occurring during any study phase (i.e., screening, run-in, 
treatment, wash-out, follow-up), at any dose of the study drugs that fulfils one or more of the 
following criteria: 
- 
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- 
Is life-threatening 
- 
Requires in-patient hospitalization or prolongation of existing hospitalization  
- 
Results in persistent or significant disability or incapacity  
- 
Is a congenital abnormality or birth defect in offspring of the patient 
- 
Is an important medical event that may jeopardize the patient or may require medical 
intervention to prevent one of the outcomes listed above. 
 
The terms disability and incapacity correspond to any temporary or permanent physical or mental 
handicap that is clinically significant and affects the patient's physical activity and/or quality of life. 
Hospitalisations already scheduled before the start of the trial are not considered a serious adverse 
event. 
 
7.1.3 
Expected adverse events 
An Expected adverse event (EAE) is an effect already mentioned in the most current version of the 
applicable document used in this trial.  
Reminder: Expected serious adverse events will be submitted by the sponsor to the competent 
authorities.  
Clinical experience in 69 patients dosed with a single administration of 89Zr-girentuximab exhibited 
that less than 10% of patients experienced a mild nausea, which was considered related to the study 
medication.  Therefore, mild nausea is an expected side effect of girentuximab. 
 
7.1.4 
Unexpected adverse events 
An unexpected adverse event (UAE) is an event whose nature, severity, frequency, or course is not 
consistent with the information about the procedures and methods used in the trial, as defined in the 
Investigator's Brochure or trial documents.  
 
Reminder: Suspected Unexpected Serious Adverse Reaction (SUSAR) should be reported without delay 
in the event of death or life-threatening events, or otherwise within 15 days of the sponsor's 
notification to the competent authorities. 
For all SUSARs, the information of follow-up must be submitted in a new delay of 8 days to the 
Competent Authorities.  
 
7.1.5 
New Safety Issue 
Any new data that may lead to a reassessment of the benefit/risk ratio of the trial, or that may be 
sufficiently important to consider changes in the conduct of the study, or trial-related documents, or 
that may lead to the suspension, termination or modification of the study protocol or similar trial. 
 
7.2 
Investigator obligations 
7.2.1 
Adverse Events reporting 
Adverse Events will be recorded in the corresponding section of the e-CRF.  

 
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For this study, all adverse events related to 89Zr- Girentuximab PET/CT should be recorded in the e-
CRF from the date of administration of 89Zr- Girentuximab until 30 days after administration. 
 
7.2.2 
Serious Adverse Events (SAEs) Reporting  
 
7.2.2.1 
Reporting information to Sponsor 
Any expected or unexpected Serious Adverse Event (SAE) requires the completion of SAE form. The 
investigator must verify that the information provided on this form is accurate and clear (e.g., do not 
use abbreviations). 
 
For each reported event, the investigator will complete the SAE Form with at least:  
• 
The patient identification, 
• 
The description of the event, as clearly as possible and in medical terminology, 
• 
The intensity of the event, 
• 
The start and end date of the event, 
• 
The measures taken and whether or not corrective treatment is required, 
• 
If the trial treatment has been interrupted, 
• 
The evolution of the event. In case of a non-fatal event, the evolution have to be followed 
until the healing or the return to the previous state or the stabilization of possible after-
effects, 
• 
The causal relationship between this event and the treatment being tested or a research-
related constraint, 
• 
The causal relationship of the event with the treated pathology, another pathology or another 
treatment. 
• 
The investigator should also attach to the SAE report, whenever possible :  
 A copy of the hospitalization report or extension of hospitalization, 
 A copy of the autopsy report if necessary,  
 A copy of all additional test results performed, including any relevant negative results 
with the laboratory's normal values,  
 Any other document it deems useful and relevant.  
All these documents must be anonymized.  
 
All SAE will be followed by the investigator until complete resolution or stabilization (at a level 
acceptable to the investigator or return to the previous state) even if the patient is out of the trial. A 
final assessment will be sent to the sponsor. 
 

 
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7.2.2.2 
SAE reporting procedure 
 
All SAEs, whether or not related to the study drug/procedure (with the exception of those identified in the 
protocol as not requiring immediate reporting, see section 7.2.2.4), must be documented and 
reported to the Sponsor and the study vigilance contact (contact information below). 
Completion and reporting procedure: 
1. A SAE Form will be completed as precisely as possible, dated and signed by the investigator.  
2. This SAE Form must be sent via e-mail to both e-mail addresses bellow: 
anne.millaret@ctvigilance.fr      AND           drci.pv@ico.unicancer.fr 
E-mail title should be completed as follows: 
SAE_STUDY name_ddmmyyyy_site number-patient number_short SAE title with grade 
The competed, signed and dated SAE Form should be attached to this e-mail (in pdf format) 
3. An acknowledgment of receipt will be kept in the investigator study master file. 
 
7.2.2.3 
Notification to the sponsor 
 
The investigator must immediately (without delay) and no later than 24 hours following knowledge 
of the event, notify the sponsor pharmacovigilance unit of any SAE or any new issue defined in section 
7.1.2:  
- from informed consent signature up to 89Zr-TLX250 administration: only SAE related to the study 
procedures must be reported to the sponsor. 
- from 89Zr-TLX250 administration up to 30 days post-89Zr-TLX250 administration: all SAEs, whether 
or not related to the study drug/procedure, must be reported to the sponsor. 
All delayed Serious Adverse Events (occurring after this period) considered reasonably related to 
89Zr-TLX250 must be reported without time limit. 
Except those that are identified in the protocol as not requiring immediate reporting.  
This initial SAE notification shall be followed promptly by a detailed written follow-up report(s) until 
event resolution. 
 
7.2.2.4 
Protocol specifications  
Some events should not be considered as SAE. 
 
In this protocol, the following events are not to be considered as SAE:  
- All hospitalizations for medical or surgical treatment scheduled before study start. 
- All hospitalizations for routine treatment or monitoring of the studied pathology not associated with           
a deterioration of the patient's condition. 
- Admission for social or administrative reasons. 
- Outpatient hospitalization, 

 
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- Progressions related to the disease under study. 
- Deaths related to disease under study progression. 
 
7.3 
Sponsor obligations 
 
7.3.1 
SAE Analysis 
The sponsor should assess: 
• 
Causality of serious adverse events (all adverse events, for which there is a reasonable 
possibility that there is a causal relationship between the study drug/procedure and the event, 
should be qualified by the investigator or sponsor as reasonably  suspected adverse events. If 
the assessment by the sponsor and the investigator are different, both opinions are 
mentioned in the report to the competent authority if required). 
• 
The sponsor should qualify the SAE in suspected expected serious adverse reaction or in 
Suspected Unexpected Serious Adverse Reaction (SUSAR). The evaluation of expectedness is 
based on knowledge of the adverse reaction and the study drug/procedures. The sponsor 
should maintain detailed records of all serious adverse events reported by the investigators. 
These records will be forwarded to the National Health Authority (ANSM), upon request. 
 
7.3.2 
Relationship Scoring 
In accordance with the ICH Recommendations on the Management of Adverse Events in Clinical Trials, 
ICH E2B(R3), version of May 12, 2005, a relationship assessment should be performed for any reported 
SAE. 
EVCTM (EudraVigilance Clinical Trial Module) criteria should be used: reasonable possibility / no 
reasonable possibility. 
 
 
 
7.3.3 
Notification of SUSARs to competent authorities 
 
The sponsor should report all Suspected Unexpected Serious Adverse Reaction (SUSAR) to the EMA 
(European Medicines Agency - Eudravigilance database), the French Health Authorities (ANSM), and 
the principal investigators. 
 
In accordance with article R1123-53 of the Public Health Code, Suspected Unexpected Serious Adverse 
Reaction (SUSAR) should be reported to the competent authorities from the day the sponsor becomes 
aware of them: 
• 
Without delay for death and life-threatening SUSAR, 
• 
Until 15 calendar days for all other SUSAR. 
 
Relevant additional Follow-up information regarding SUSARs should be reported to the EMA, ANSM 
and the investigators within eight days of the initial report. 
 

 
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7.3.4 
Notification of New Safety Issue 
 
The sponsor is responsible for alerting the principal investigator in case of identification of a New 
Safety Issue and should propose urgent measures to be implemented. 
 
The sponsor is responsible for reporting to the competent authorities, without delay, any New Safety 
Issue and the proposed measures. 
 
Relevant follow-up information regarding any New Safety Issue should be reported to the competent 
authorities within a new delay of 8 days. 
 
7.3.5 
Reporting of DSURs (Development Safety Update Report) 
 
On the anniversary date of the Health Authorities trial authorization, the sponsor should report an 
Annual Safety Report (ASR) consisting of three parts: 
• 
Part 1: Analysis of patient safety. 
• 
Part 2: the list of all suspected serious adverse events (including unexpected serious adverse 
events) that occurred in the trial in France (and abroad, including in third countries) during 
the period covered by the report. 
• 
Part 3: summary tables of all serious adverse events and serious adverse reactions that have 
occurred in the trial since the study start. 
This report is sent to the competent authorities (ANSM), Ethics Committee (CPP) and principal 
investigators within 60 days of the anniversary date of the trial authorization. 
 
7.3.6 
Reporting of other safety data 
 
The sponsor should report any safety data or new safety event to the competent authorities (ANSM 
and CPP) as soon as possible and no later than 15 calendar days from the first time the sponsor 
became aware of the minimum information for immediate reporting. 
 
Relevant additional information must be transmitted within 8 days and 15 days new delay. 
 
7.3.7 
In utero exposure 
 
If a patient becomes pregnant during the study, the pregnancy must be reported to the sponsor within 
a time frame defined by the sponsor. 
The investigator informs the sponsor using a standard "Initial Pregnancy Data Collection" sheet. This 
form should include the expected date of delivery, the contact details of the obstetrician and of the 
planned maternity hospital if the pregnancy is ongoing.  
 
 The investigator should follow the patient until completion of the pregnancy and should notify the 
sponsor of the outcome using a standard pregnancy outcome form. 
 
If the outcome of the pregnancy meets the criteria for immediate classification as an SAE (i.e., 
postpartum complication, spontaneous abortion, stillbirth, neonatal death, or congenital anomaly), 
the investigator should follow the procedures for reporting an SAE. 
 

 
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8. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION  
 
The analysis will cover 12 patients. 
 
8.1 
Brief reminder of study objectives 
 
8.1.1 
Primary objective 
 
To assess the concordance for tumor lesion detection using 89Zr-TLX250 PET/CT versus a conventional 
18FDG PET/CT scan where comparison will be made on a per lesion analysis basis. 
 
 
8.1.2 
Endpoints of primary objective 
 
Concordance study of metastatic uptake seen in 18FDG PET/CT scan and 89Zr-TLX250 PET/CT scan per 
"lesion" by comparing for each lesion the CT scan, 18FDG PET scan and 89Zr-TLX250 PET/CT scan by 
assessing a ratio "Number of positive or negative 89Zr-TLX250 lesions / Number of positive or negative 
FDG lesions” and "Number of positive or negative 89Zr-TLX250 lesions / Number of CT scan lesions”. 
 
8.1.3 
Secondary objectives 
 
4. To determine the percent of total tumor burden (whole body) detected on 89Zr-TLX250 
PET/CT scan compared to that defined on 18FDG PET/CT used as the reference. 
5. To assess the correlation between the normalized uptake values (SUV) of 89Zr-TLX250 and 
CAIX histological expression if a biopsy is done. 
6. To confirm the perfect safety and tolerability of 89Zr-TLX250 and assess the generation of 
human anti-chimeric antibodies in response to the girentuximab. 
 
8.1.4 
Endpoints of secondary objectives 
 
4. Percent of positive CA IX metastatic tumor burden compared to total metastatic tumor 
burden by 18FDG (ratio "Number of positive 89Zr-TLX250 lesions / Number of positive FDG 
lesions") 
5. If a metastasis biopsy is conducted, assessment of the correlation between the normalized 
uptake values (SUV) of 89Zr-TLX250 positive lesions and CAIX histological expression will 
be 
done 
by 
comparing 
the 
89Zr-TLX250 
semi-quantitative 
data 
with 
the 
immunohistochemical results (IHC) of biopsied metastases. 
6. The safety and tolerability of 89Zr-TLX250 will be evaluated by measuring and monitoring 
vital signs within 2 hours after injection of the radiopharmaceutical. The patient will be 
informed that in the event of abnormal physical signs, occurring within 24 hours after 89Zr-
TLX250 administration, he must report them to the investigator for registration. The 
reporting period of AEs (related to 89Zr-TLX250) and SAEs cover a period of 30 days after 
89Zr-TLX250 administration. 

 
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 The NCI Common Toxicity Criteria, version 5.0 reference will be used. 
 HACA (Human anti-chimeric antibody) will be assessed. 
 
8.1.5 
Exploratory objectives 
 
For 5-6 patients, assessment of the absorbed doses received by organ and in whole body after 89Zr-
TLX250 administration for imaging purpose in metastatic TNBC patients. 
 
For these patients, blood samples will be drawn at D0 (before 89Zr-TLX250 administration), D1, D3, D5 
and D7. 
Each sample will be analyzed for serum 89Zr radioactivity levels in the local nuclear medicine 
department.  
 
 
8.1.6 
Endpoints of Exploratory objectives 
 
For 5-6 patients, quantitative biodistribution of 89Zr-TLX250 evaluated from sequential whole body 
PET-CT imaging D0, D1, D3, D5 and D7 and pharmacokinetic data (blood samples taken before 
injection and at the same time of imaging). 
 
8.2 
Determination of sample size 
 
As this study is a proof-of-concept, exploratory and descriptive pilot study, the sample size 
determination is not based on statistical considerations, it is planned to enrol 12 evaluable patients. 
 
8.3 
Selection of patients to be included in the statistical analysis 
 
All included patients will be analysed. 
 
8.4 
Study feasibility 
 
The estimated duration of study recruitment is approximately 12 months. 
 
8.5 
Interim analyses 
 
Not applicable. 
 

 
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8.6 
Statistical criteria for study termination 
 
Not applicable. 
 
8.7 
Handling of missing, unused or invalid data 
 
Special care will be taken to minimize any missing data for the 12 patients enrolled. 
 
8.8 
Description of analysis sets 
 
8.8.1 
For Safety Analysis Set:  
 
The frequency and severity of the clinical and biological effects collected over a period of 15 days then 
at 3 months following the completion of the 89Zr-TLX250 PET/CT will be described by means of 
frequency of their respective modalities. HACA test at the visit at 3 months post 89Zr-TLX250 PET/CT. 
 
 
8.8.2 
For the determination of 89Zr-TLX250 PET-CT preliminary analysis of 
diagnostic performance:  
 
From the reference ("gold standard") determined for each patient from all imaging and histology 
screening data and/or 3-months imaging follow-up (RECIST 1.1 criteria, or PERSIST criteria). The 
reporting qualitative and semi-quantitative parameters of the lesions will be established at D5 post-
injection. The diagnostic performance of 89Zr-TLX250 PET/CT obtained at the post-injection delay 
considered optimal related, 18FDG PET/CT scan and CT scan compared to gold standard will be 
described by the sensitivity, specificity, positive and negative predictive values (with their 95% CI) and 
compared by means of Mc Nemar test. Concordance between techniques will be described by means 
of Kappa.  
 
Total number of lesions (gold-standard) will be the number of lesions identified by at least one 
modality. 
 
Lesion detection rates per imaging modality and combined imaging modalities (CT combined with PET) 
will be estimated with their 95% CI and compared by Wald test, overall and according to organ sites.  
 
Agreement in detecting lesions between modalities will be assessed using kappa’s (95%CI). 
 
Furthermore, we will compare the median number of affected organ sites across patients assessed by 
18FDG-PET/CT or 89Zr-girentuximab-PET/CT using Wilcoxon signed rank tests. 
 
The physiological biodistribution of 89Zr-girentuximab will be described in normal tissues (lung, liver) 
using geometric mean SUVmean. 
 

 
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The overall geometric mean 89Zr-girentuximab or 18FDG SUVmax will be used to quantify uptake in 
lesions. Link between uptake and lesions location and lesions diameter on CT will be tested. 
 
Correlation between 18FDG -uptake and 89Zr-girentuximab-uptake will be calculated by Rho’s 
coefficient (Spearman test). 
 
 
8.8.3 
For ancillary study set:  
The dose received for healthy tissues, the effective dose received for the whole body from 
sequential whole-body imaging and pharmacokinetic data (at D0, D1, D3 and D7) will be described 
by means of mean, standard deviation, median, minimum, maximum and interquartile range. 
 
8.9 
Managing changes to the analysis sets 
 
Not applicable. 
  
 

 
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9. 
CONTROL AND QUALITY ASSURANCE  
 
9.1 
Oversight Committees 
 
9.1.1 
Independent data monitoring committee 
Not applicable. 
 
9.1.2 
Steering Executive Committee  
Not applicable. 
 
9.2 
Quality assurance 
 
9.2.1 
Study monitoring 
 
In order to guarantee the authenticity and credibility of the data in accordance with the GCP of 24 
November 2006, the sponsor is setting up a quality assurance system which includes: 
• 
The management and monitoring of the trial according to the procedures of the ICO, Clinical 
Research Department. 
• 
The quality control of the data from the investigator site by the monitor whose role is: 
 To check compliance with the protocol, GCP and the APPLICABLE laws and regulations, 
 To check the consent and eligibility of the patients participating to the trial, 
 To check the concordance and consistency of the CRF data compared to source 
documents,  
 To check the notification of serious adverse events, 
 To monitor the tracking of the study treatments (dispensing, storage and 
accountability of study treatments), 
 To ensure that patients who may be suitable for research are not already participating 
in research that might make it impossible to include them in the proposed research. 
The monitor also ensures that patients have not participated in research for which an 
exclusion period is currently required. 
• 
The audit of the participating investigational sites when deemed necessary, 
 
The monitors in charge of quality control of this study are duly mandated for this purpose by the 
sponsor and must have access to the patients data, strictly required for this control. The monitors are 
bound by professional secrecy under the conditions defined by articles 226-13 and 226-14 of the penal 
code. The tracking of monitoring visits is ensured by a written monitoring report. 
 

 
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In order to ensure the optimal research quality control, the investigator commits to provide the monitor with 
direct access to all patient files.  
The same applies to representatives of the health authorities. 
 
9.2.2 
Monitoring Plan 
 
The monitoring plan is established by the study team and the responsible institution according to the 
study objectives. 
 
The frequency of visits will depend on the number of patients enrolled, the rate of inclusion and the 
difficulties observed during the study. 
 
Monitoring will be carried out by the Clinical Research Promotion Department of the ʺInstitut de 
Cancérologie de l’Ouestʺ. A Clinical Research Associate (CRA) will visit each site in order to carry out 
quality control of the data reported in the case report forms.  
On-site monitoring visits will be organised after an appointment with the investigator. The CRAs must 
be able to consult: 
• 
The eCRF of patients enrolled,  
• 
Patients' medical and nursing files,  
• 
The investigator file. 
The protocol has been classified according to risk level D with a "LIR" score of 8: The level of monitoring 
required is High:  
100 % of patient files will be monitored at 100%.  
Monitoring will be carried out as follows:  
Each enrolling site will be monitored at least once (on-site and/or remote visit), with the following 
data collected:  
1) The existence of patients enrolled. 
2) The collection and archiving of signed informed consents.  
3) Compliance with the eligibility criteria (inclusion and non-inclusion). 
4) The presence of the primary objective endpoint:  
 Concordance evaluation of metastatic uptake seen in CT scan, 18FDG PET/CT scan and 89Zr-
TLX250 PET/CT scan per "lesion".  
5) The presence of the major secondary objective endpoints:  
 Percent of positive CA IX metastatic tumor burden compared to total metastatic 
tumor burden by 18FDG (ratio "Number of positive 89Zr-TLX250 lesions / Number of 
positive FDG lesions") 
 If a metastasis biopsy is realized, assessment of the correlation between the 
normalized uptake values (SUV) of 89Zr-TLX250 positive lesions and CAIX histological 
expression.  
6) Reporting and monitoring of Adverse Events  

 
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a) Serious Adverse Events  
b) New Safety Event 
 
9.2.3 
Inspection / Audits 
 
As part of its audit program, the sponsor may need to audit some investigational sites. The site and 
the investigator agree that audits are carried out by Sponsor or any person duly authorised for at least 
ten years after the trial. 
More generally, the investigator site and the investigator undertake to devote all necessary time to 
audit procedures, control and additional information requested by the sponsor or by a Concerned 
Competent Authority. 
 
 
 

 
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10. 
ETHICAL AND REGULATORY CONSIDERATIONS 
 
The clinical trial must be conducted in accordance with: 
The current Declaration of Helsinki. The ICH Guidelines for Good Clinical Practices (E6) and the French 
national regulatory requirements: 
• 
Le Code de la Santé Publique. 
• 
La Loi n°2004-806 du 9 août 2004 relative à la politique de santé publique portant notamment 
transposition de la directive européenne n°2001/20/CE du 4 avril 2001 et la loi n°2006-450 du 
18 avril 2006. 
• 
La Loi Jardé n°2012-300 du 12 mars 2012 (décret d’application du 16 novembre 2016) 
concernant la recherche sur la personne humaine). 
• 
La Loi n°2011-814 du 7 juillet 2011 relative à la bioéthique. 
• 
La Loi n° 78-17 du 6 janvier 1978 relative à l’informatique aux fichiers et aux libertés, modifiée 
notamment par la Loi n° 204-801 du 6 août 2004 et la loi n°2018-493 du 20 juin 2018, dans sa 
version en vigueur au moment de la réalisation de l’Essai. 
• 
Le Règlement (UE) n°2016/679 du 27 avril 2016 relatif à la protection des données 
personnelles (RGPD). 
  
10.1 
Clinical trial authorisation 
 
The protocol has been submitted to the Committee for the Independent Ethic Committee (IEC) “CPP 
SUD EST VI (Clermont Ferrand)”, and received a written approval. 
 
The protocol has been submitted to the National health Authority (ANSM) and received a written 
approval. 
 
10.2 
Patient Information and Consent  
 
Prior to the participation of a patient in the trial, this patient will be about the trial. The patient written 
consent must be obtained after the investigator has given him/her full information. 
The consent form must be dated and signed personally by the patient and the investigator. The original 
will be filed in the investigator's binder and the duplicate will be given to the patient. 
 
10.3 
Sponsor responsibilities 
 
The “Institut de Cancérologie de l’Ouest” (ICO), as sponsor and initiator of this trial, is accountable for 
trial management and for verifying that the financing schedule covers the anticipated expenses of the 
trial. 
The main sponsor responsibilities are: 

 
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• 
The subscription of a civil-responsibility insurance; 
• 
The obtaining of an ID RCB identification number and registration of the trial in the European 
Drug Regulatory Authorities Clinical Trials database. 
• 
The obtaining of the authorization of Ethics committee (IEC) and ANSM on the initial protocol 
and possible amendments when applicable. 
• 
The notification of any suspected (unexpected) serious adverse reactions (SUSAR), according 
to the local regulatory requirements, to the respective regulatory authorities, and the 
notification of this information to the IEC and the investigators of the study. 
• 
The transmission of the Development Safety Update Reports (DSUR) to the respective 
regulatory authorities and to the IEC according to the local regulatory requirements. 
• 
The information about the study to the investigational sites institutions, pharmacists and 
investigators, according to local regulatory requirements. 
• 
The notification of the beginning and the end of the study to the respective competent 
authorities and to the IEC, according to the local regulatory requirements. 
• 
Writing the final report of the trial and forwarding the summary to the ANSM. 
• 
The information on the study’s results, according to local regulatory requirements, to the 
respective Competent Authorities, to the IEC to the research participant. 
• 
The archiving of the study’s essential documents for a minimal duration of 15 years after the 
research has ended. 
 
10.4 
Investigator responsibilities 
 
The principal investigator of each investigational site participating in the trial commits to conduct the 
trial as specified in this protocol and in accordance with the current regulatory requirements, and in 
particular the current Guideline for Good Clinical Practice of 24 November 2006. 
 
It is the responsibility of the principal investigator to: 
• 
Provide to the sponsor with her/his own curriculum vitae (CV) and those of his/her 
collaborators. 
• 
Identify the members of his/her team who participate in the trial and to define their individual 
responsibilities. 
• 
Start recruiting patients after approval of the sponsor. 
• 
Be available for monitoring visits, audits and investigator meetings. 
 
It is the responsibility of each investigator to: 
• 
Ensure the confidentiality of all data recorded during the trial. 
• 
Collect the informed consent, written, dated and signed personally by each individual research 
participant before any specific selection procedure to the trial (to be documented in the 
patient file). 

 
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• 
Regularly complete the case report form (CRF) for each of the patients included in the trial 
and allow the clinical research assistant (CRA) mandated by the sponsor to have direct access 
to the source documents in order to validated the data collected in the CRF. 
• 
Declare to the sponsor as soon as he becomes aware of any serious adverse event occurring 
during the trial. 
• 
Accept regular visits by the CRA and possibly those of auditors as mandated by the sponsor or 
the inspectors of the respective regulatory authorities. 
• 
Date, correct and sign the corrections made in the CRF and the requests of the data correction 
forms (DCF). 
 
10.5 
Human biological samples collection 
 
Non applicable. 
 
10.6 
Patient Committees 
 
The sponsor has asked the Committee of the “Ligue contre le Cancer” to proof-read the information 
note. 
The aim of the Ligue contre le Cancer's patient committee is to reread the clinical trial protocols in 
cancerology. Created in 1998, the Patients' Committee brings together patients from the League's 
departmental committees and cancer patient associations. 
It can be consulted, in particular for the purpose of reviewing information notes intended for patients. 
These reviews help to improve the legibility, acceptability and clarity of the information provided to 
patients and to facilitate decision-making for the patients concerned, thanks to the quality of the 
information. 
 
 

 
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11. 
COLLECTION AND MANAGEMENT OF RESEARCH DATA 
 
11.1 
Collection of study data 
 
11.1.1 
Collection and conservation of study data  
The data will be collected via an electronic Case Report Form (eCRF) accessible from a secure internet 
connection, allowing traceability of data access and modifications. 
 
A Case Report Form (eCRF) will be created per patient. All the information required by the protocol 
must be provided in the CRF within 15 days following its availability. The CRF will include the data 
needed for statistical analyses based on the study objectives, as well as the data needed to detect 
major deviations from the protocol (inclusion and non-inclusion criteria, premature discontinuation 
and causes, follow-up of protocol visits and examinations, collection of adverse events and 
concomitant treatments). 
Data entry will be performed online by Investigators and authorised staff identified in the Delegation 
of Responsibilities Form for each site. This form is kept in the investigator Master file. 
 
The study data are under the responsibility of the Director of “Institut de Cancérologie de l’Ouest”. 
 
Until the results are published, the study data will be hosted on a centralised server provided by the 
company ENNOV. An ISO 9001:2008 approved bi-site data hosting centre ensures data storage, 
protection and security (Data Centre in Poitiers and Roubaix, mirror sites). Exports are carried out in 
parallel in a secure area of the ICO's information system servers for carrying out analyses. 
 
The study data and essential documents will then be archived for a minimum period of 15 years, 
either on the ICO's premises or with a service provider specialising in medical archiving. 
 
11.1.2 
Identification of all source data not contained in the patient medical file 
 
Not applicable. 
 
11.1.3 
Data coding 
 
By signing this protocol, the principal investigator and all co-investigators undertake to keep 
confidential the identities of the patients enrolled in the study.  
 
Patients will be identified by an identification code assigned directly from the electronic CRF during 
the enrolment procedure. This identifier will be composed of the patient's initials, i.e. the first letter 
of the surname and first name, supplemented by a number assigned at the time of the patient's 
enrolment. 
This unique identifier code will be the only information that will appear on the CRF and will allow the 
CRF to be linked to the patient's identity afterwards. 

 
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The sponsor is also required to provide the necessary elements for the de-identification of any 
documents in its possession (reports of imaging or biological reports, etc.) that may be attached to 
the CRF.  
 
11.2 
Study Data Processing  
 
11.2.1 
By the Sponsor 
 
The processing of the study data is carried out by the Clinical Research department (DRCI) of the ICO, 
in the Data Factory Unit, under the responsibility of François Bocquet; the data being the property of 
the ICO, the sponsor of the research. 
 
The data processing software is ENNOV CLINICAL, Excel, R, Stata and SAS. 
 
In accordance with Deliberation No. 2018-153 of 3 May 2018 approving a reference methodology 
relating to the processing of personal data (implemented within the framework of research in the field 
of health with the consent of the person concerned), the ICO has undertaken to follow the MR001 
reference methodology of the National Commission for Information Technology and Civil Liberties. 
This processing has been registered in the register file held at the disposal of the “Commission 
Nationale de l'Informatique et des Libertés (CNIL)” under number 285. 
 
11.2.2 
By sites, in the case of a computerised medical file is used 
 
If the data needed for research within the sites are processed or managed by computerised systems, 
each site must: 
 
a) Ensure and document that the computerised systems used in the research comply with the 
requirements in terms of data integrity, accuracy, reliability and performance (i.e. validation); 
b) Establish and monitor standard operating procedures for the use of such systems; 
c) Ensure that these systems allow modifications of the collected data, that each modification is 
automatically authentified, and that the data cannot be removed  (i.e. maintain an audit trail 
of data and changes); 
d) Establish and maintain a security control system that prevents unauthorised access to data; 
e) Maintains a list of persons authorised to modify the data; 
f) Carry out appropriate backups of the data; 
g) Preserves the blinding, where appropriate (e.g. when entering and processing data); 
h) Ensures that the processing of personal data implemented in the research is carried out under 
the conditions defined by Law No. 78-17 of 6 January 1978 relating to information technology, 
files and liberties as amended and the regulatory texts adopted for its application, as well as 
by the General Regulations on data protection . 
 
If the data are transformed while being processed, it should always be possible to compare them with 
the original observations/records. 
 
The computerized system used to identify the patients participating in the trial must not be ambiguous 
and should allow the identification of all data collected for each patient while preserving their 
confidentiality in compliance with amended Law no. 78-17. 

 
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11.2.3 
Retention of documents 
 
All documentation relating to the trial (protocol, consents, case report forms, correction requests, 
investigator file, etc.), as well as the original documents (laboratory results, radiology, consultation 
reports, clinical examination reports, etc.) are considered confidential and must be kept in a secured 
place.  
For each site and according to the national regulatory requirements (order of 08 November 2006), the 
Principal Investigator must keep the data as well as a patient identification list for a minimum of 15 
years after the end of the study. At the end of this period, the site may only destroy this 
documentation after the sponsor has given its written authorization. 
 
 
 
 

 
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12. 
CONFIDENTIALITY AND OWNERSHIP OF DATA 
 
All the information communicated or obtained and all the data and results generated during the trial 
are the sole and exclusive property of the sponsor: “Institut de Cancérologie de l’Ouest”, which may 
freely dispose of them. No oral or written communication concerning the study data may be made 
without the agreement of the sponsor. 
 
The investigator undertakes, for himself and for all persons involved in the trial, to guarantee the 
confidentiality of all information provided by the ICO until publication of the trial results. This 
obligation of confidentiality will not apply to any information that the investigator may have to 
communicate to patients concerning their participation in the trial, nor to information already 
published. 
 
The investigator undertakes not to publish, disclose or use in any way, directly or indirectly, scientific 
or technical information related to the trial.  
 
Nevertheless, in accordance with article R 5121-13 of the Public Health Code, the site and the 
investigator may provide information relating to the trial: 
• 
To the Minister in charge of Health. 
• 
Public health inspectors. 
• 
Pharmacist’s public health inspectors. 
• 
To the Director General and ANSM inspectors. 
 
 
 

 
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13. 
PUBLICATION AND VALORISATION RULES 
 
The results of this study will be submitted for publication(s) and/or communication (s).  
 
All information resulting from this research project is considered confidential, at least until 
appropriate analysis and control by the sponsor, the coordinating investigator, data manager and trial 
statistician is completed. 
A clinical study report will be prepared by the sponsor and sent to the study participating investigators.  
 
Any scientific communication (abstract/publication, poster, presentation/communication (oral or 
written), manuscript, intranet, extranet, etc.) including the results of the research project should be 
submitted to the sponsor (ICO) for approval. 
 
For each publication/communication, the ICO will be designated as Sponsor and the funder (SIRIC) 
will be explicitly mentioned. 
 
 
According to the international rules of authorship, (L’intégrité scientifique à l’INSERM, SIGNATURE DES 
PUBLICATIONS SCIENTIFIQUES, les bonnes pratiques, 2018, the authors who participated actively will 
be cited, i.e.: 
 
- 
substantial contribution to the design of the project and the experimental protocol, to the 
conception of the results, and/or to the analysis and interpretation of the results; 
- 
Drafting the work or revising it critically for important intellectual content;  
- 
explicitly approve the final version of the manuscript, both the scientific content and the 
authors list, and thus directly engage their responsibility; this is also a requirement of the 
publishers. 
 
Those who have contributed to the work without meeting the three criteria should be thanked at the 
end of the article, with their agreement.  
 
Thus, for every publication, the order of authors will be defined by the sponsor (ICO) and the 
coordinating investigator. 
 
 
Rank among the authors 
Project coordinator or sponsor representative  
1st author or Last author 
Investigators  
2nd author / 3rd author and more 
(cited according to their rank of 
recruitment/inclusion in the study  
Statistician 
Penultimate or last author 
A representative of Telix Pharmaceutical 
 
 
Any conflict regarding author’s name appearance will be submitted to the sponsor (ICO) decision. 
In the event of ancillary studies (biological or other): Specific publications may be produced; they 
should cite the publication of the main study as a reference. These publications should be submitted 
to the coordinating Investigator and the sponsor for approval.  

 
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They will include the name of the person who carried out the side job as well as the names of all other 
persons involved in the side job. 
In addition, all communications, manuscripts or presentations must include a heading which 
imperatively mentions the ICO, all institutions, investigators and cooperating groups, the learned 
societies, the partners who contributed to the project, as well as the organisations that financially 
supported the research. 
In addition, in order to be fully involved and to be able to consent to it, the sponsor will be notified in 
advance of any dissemination of data in Open Research Data, any commercial exploitation and/or 
patent filing procedures that are relevant to this research project. 
 
 

 
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14. 
FINANCIAL ASPECTS 
 
The study is funded by SIRIC ILIAD. 
 
TELIX Pharmaceutical support this study by providing the study drug: 89Zr-TLX250 (carrier-free) for all 
12 patients.  
 

 
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LIST OF APPENDIX 
 
 
Appendix 1: Synopsis 
 
Appendix 2: Investigators list 
 
Appendix 3: Informed consent form 
 
Appendix 4: SAE Form 
 
Appendix 5: NCI-CTCAE V5.0 form 
 
Appendix 6: Patient Card