A Pilot Open-label, Feasibility Study to Assess safEty, Tolerability, Radiation Dosimetry, and Imaging Properties of 89Zr-labeled giRenTuximab (89Zr-Girentuximab) in patIents With Non-musclE-iNvasive Bladder CancEr (NMIBC)
Phase: EARLY_PHASE1
Conditions: Bladder Cancer
Sponsor: Institut Cancerologie de l'Ouest

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PERTINENCE 
 
ʺA Pilot open-label, feasibility study to assess safEty, tolerability, radiation 
dosimetry, and imaging properties of 89Zr-labeled giRenTuximab (89Zr-
Girentuximab) in patIents with Non-musclE-iNvasive bladder CancEr (NMIBC)ʺ 
 
 
 
N° EUDRACT: 
2021-001709-61 
Ref ICO: 
 
ICO-2021-03 
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 
 
 
 
Scientific 
Coordinator 
 
Dr Jean François CHATAL, MD 
Head of Medical Affairs  
ATONCO 
Email : jf.chatal@atonco-pharma.com 
 
 
 
Methodologist 
 
Dr Loïc Campion, MD And Elodie Martin MSc 
Oncology Data Factory and Analytics  
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  
and  
elodie.martin@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: 
 
 
 
 
 
 
 

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CLINICAL TRIAL AUTHORIZATION 
PROTOCOL PERTINENCE  
 
ʺA pilot open-label, feasibility study to assess safety, tolerability, radiation dosimetry, and imaging 
properties of 89Zr-labeled girentuximab (89Zr-Girentuximab) in patients with Non-muscle-invasive bladder 
cancer (NMIBC)ʺ 
 
CLINICAL TRIAL AUTHORIZATION 
Agence Nationale de Sécurité du Médicament et des Produits 
de Santé (ANSM): 
Date of authorization: 29/06/2021 
Ref. ANSM (IDRCB) : MEDAECNAT-2021-05-
0022_2021-001709-61 
Ethics committee : 
COMITE DE PROTECTION DES PERSONNES ILE DE FRANCE III 
Date of approval: 07/06/2021 
Ref. CPP  : 3917 I 
Réf CNRIPH : 21.05.10.47712 
 
 
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 Jean François CHATAL, MD 
Sientific Coordinator 
 
Head of Medical Affairs  
ATONCO 
Email : jf.chatal@atonco-pharma.com 
Dr Loïc Campion, MD 
And Elodie Martin MSc 
Methodologist 
 
Oncology Data Factory and Analytics  
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  & 
elodie.martin@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 
 

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SPONSOR REPRESENTATIVE 
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 radiopharmaceutical for the imaging of Non-muscle-invasive bladder 
cancer (NMIBC) patients. 
 
One of the objectives of this study is to assess the biodistribution in whole body and the safety of 89Zr-
girentuximab when it is injected in bladder.  
After establishing the targeting properties of 89Zr-Girentuximab PET/CT imaging radiopharmaceutical in 
NMIBC, it should be interesting to develop a new targeted therapy using girentuximab- radiolabelled with a 
therapeutic radionuclide such as Astatine-211 (211At-Girentuximab) to treat NMIBC.  
An alpha-immunotherapy project of non-muscle-invasive bladder cancer was initiated by ATONCO with anti-
CAIX girentuximab labeled with Astatine-211. 
 
 
 
 

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ABBREVIATIONS AND DEFINITION OF TERMS 
The following abbreviations and special terms are used in this study Clinical Study Protocol. 
 
211At 
Astatine-211 
213Bi 
Bismuth-213 
18F 
Fluor-18 
111In 
Indium-111 
124In 
Indium-124 
89Zr 
Zirconium-89 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase / Glutamic Pyruvic Transaminase (GPT) 
ANSM 
French Health Authority 
AST 
Aspartate Aminotransferase / Glutamic Oxaloacetic Transaminase (GOT) 
Β-HCG 
Beta human chorionic gonadotropin 
BP 
Blood Pressure 
bpm 
beats per minute 
CA IX 
Carbonic anhydrase IX 
Cmax 
Maximum Concentration 
CFR 
Code of Federal Regulations 
CPP 
French Ethics Committee 
CRF 
Case Report Form 
CT 
Computed tomography 
CV 
Coefficient of Variation 
CL 
Clearance 
DSUR 
Development Safety Update Reports 
EC 
Ethics Committee 
eCRF 
Electronic case report form 
EMA 
European Medicines Agency 
EOS 
End Of Study 
EVCTM 
EudraVigilance Clinical Trial Module 
FDG 
Fluorodésoxyglucose 
FU 
Follow up 
GCP 
Good Clinical Practices 
GMP 
Good Manufacturing Practices 

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GLP 
Good Laboratory Practice 
HACA 
Human Anti-Chimeric Antibodies 
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  
NMIBC 
Non-muscle-invasive bladder cancer  
PET/CT 
Positron emission tomography-computed tomography 
PSCA 
Potential clinically significant abnormalities 
PK 
Pharmacokinetic(s) 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
SE 
Standard Error 
SID 
Subject identification 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
SUV 
Standardized uptake value 
TEAE 
Treatment-emergent adverse event 
t1/2 
Terminal half-life 
TURBT 
TransUrethral Resection of Bladder Tumor  
UAE 
Unexpected Adverse Event 
VD 
Distribution volume 
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 25/06/2021 
Initial authorized version 
Substantiel Amendment N°1 
V2 03/01/2022 
Intravesical instillation pocedure modified 
 
 
 
 
 
 
 
 
 
 
 
 

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TRIAL CALENDAR 
 
NUMBER OF EXPECTED PATIENTS 
6 patients 
DURATION OF ENROLMENT PERIOD : 
12 months 
DURATION OF PROCEDURE / DURATION OF FOLLOW-UP : 
2 days / 30 days 
MAXIMUM TIME OF PARTICIPATION PER PATIENT : 
30 days 
GLOBAL DURATION OF THE TRIAL : 
13 months 
END OF THE CLINICAL TRIAL : 
Last visit of the last enrolled patient 
 
 
 
CONSIDERED DURATION UNTIL THE ANALYSIS OF THE 
PRIMARY OBJECTIVE :  
25 months (13 + 12 months data analysis) 
INTERIM ANALYSIS : 
NA 
 
 
 

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SCHEDULE OF STUDY ASSESSMENTS  
 
Period 
Screening 
Study procedure 
Follow-up 
Visit 
Screening  
Day 0 
Day 1 
Day 2 
Day 30 
Visit number 
1 
2 
3 
4 
5 
6 
76 
Study day 
-30 to 0 
 T0-2H 
T0 
T0+ 2H  
T0+20H 
T0+44H 
Day 30 (±5)  
Written Informed consent 
X 
 
 
 
 
 
 
Medical and disease  history 
X 
 
 
 
 
 
 
Physical Exam 
Physical exam, height, Weight, performance status 
X 
 
 
 
 
 
X7 
Vital signs (temperature, Blood Pressure/Pulse)  
X 
X 
 
X 
 
 
 
Laboratory Exam 
Haematology/ Biochemistry 
X  
 
 
 
X 
 
 
Serum or urine Pregnancy test (if applicable) 
X 
 
 
 
 
 
 
Urine cytobacteriological testing  
X1 
 
 
 
 
 
X 
Urine dipstick analysis 
 
X8 
 
 
X 
X 
 
Imaging 
Cystoscopy report 
X 
 
 
 
 
 
 
89Zr-Girentuximab PET/CT (Administration and Imaging) 
89Zr-girentuximab intravesical instillation 
 
X 
 
 
 
 
 
PET/CT imaging whole body  
 
 
 
X3 
 
X4 
 
Bladder PET/CT imaging  
 
 
X2 
 
X 
X5 
 
Blood sampling for 89Zr-    Girentuximab    dosing  
 
 
 
 
X 
 
 
Immuno-Histological Analysis 
Bladder tumor from TransUrethral Resection of 
Bladder Tumor (TURBT) or cystectomy 
X 
 
 
 
 
 
X 
Safety 
Concomitant medications 
X 
X 
 
X 
X 
X 
X 
Adverse Events 
X 
X 
 
X 
X 
X 
X 
Serious Adverse Events 
X 
X 
 
X 
X 
X 
X 
1. 
Negative urine cytobacteriological testing or Sterile urine culture 10 days before intravesical instillation (as far as possible before 89Zr-girentuximab ordering) 
2. 
At the end of 89Zr-girentuximab administration: 2 hours after intravesical instillation (see intravesical instillation procedure). 
3. 
2 hours after 89Zr-girentuximab administration: 4 hours after intravesical instillation. 
4. 
A Whole body scan should be performed only if blood radioactivity testing on day 1 is positive.  
5. 
A bladder PET/CT imaging should be performed only if blood radioactivity testing on day 1 is negative. 
6. 
Visit on site or teleconsultation. 
7. 
Performance Status should be assessed. 
8. 
To be performed before 89Zr-girentuximab administration 
 
 
 
 

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TABLE OF CONTENTS 
PAGE 
 
PROTOCOL SYNOPSIS ______________________________________________________ 5 
ABBREVIATIONS AND DEFINITION OF TERMS __________________________________ 6 
HISTORY OF PROTOCOLE AMENDMENTS ______________________________________ 8 
TRIAL CALENDAR _________________________________________________________ 9 
SCHEDULE OF STUDY ASSESSMENTS _________________________________________ 10 
TABLE OF CONTENTS _____________________________________________________ 11 
1. 
INTRODUCTION ______________________________________________________ 15 
1.1 
Disease background ____________________________________________________ 15 
1.2 
Procedure Background _________________________________________________ 16 
1.2.1 
Girentuximab ________________________________________________________________ 16 
1.2.2 
89Zr-girentuximab ____________________________________________________________ 17 
1.2.3 
Effects in Humans ____________________________________________________________ 28 
1.3 
Rationale for conducting this study _______________________________________ 43 
1.4 
Benefit/risk and ethical assessment _______________________________________ 44 
1.4.1 
Individual benefit _____________________________________________________________ 44 
1.4.2 
Collective benefit _____________________________________________________________ 44 
1.4.3 
Overall risks _________________________________________________________________ 44 
1.4.4 
Benefit / risk balance __________________________________________________________ 45 
2. 
OBJECTIVES _________________________________________________________ 47 
2.1 
Primary objective(s) and endpoint ________________________________________ 47 
2.1.1 
Primary objective _____________________________________________________________ 47 
2.1.2 
Endpoints of primary objective __________________________________________________ 47 
2.2 
Secondary objective(s) and endpoint ______________________________________ 47 
2.2.1 
Secondary objectives __________________________________________________________ 47 
2.2.2 
Endpoints of secondary objectives _______________________________________________ 47 
3. 
PATIENT SELECTION __________________________________________________ 49 
3.1 
Population description _________________________________________________ 49 
3.2 
Inclusion criteria ______________________________________________________ 49 
3.3 
Non-inclusion criteria __________________________________________________ 49 
3.4 
Withdrawal of patients from study _______________________________________ 50 
3.4.1 
Permanent discontinuation of procedure _________________________________________ 50 
3.4.2 
Withdrawal of consent ________________________________________________________ 51 
3.5 
Patients replacement __________________________________________________ 51 

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4. 
STUDY PROCEDURE 89Zr-TLX250 PET/CT SCAN _____________________________ 52 
4.1 
Study drug 89Zr-TLX250 _________________________________________________ 52 
4.1.1 
Chemical Properties __________________________________________________________ 52 
4.1.2 
Pharmaceutical Properties _____________________________________________________ 52 
4.1.3 
Storage and Handling _________________________________________________________ 52 
4.1.4 
Packaging and Labelling _______________________________________________________ 52 
4.1.5 
Drug Logistics and Accountability ________________________________________________ 53 
4.2 
Study procedure: 89Zr-TLX250 PET/CT Imaging_______________________________ 54 
4.2.1 
Dosage and Administration _____________________________________________________ 54 
4.2.2 
89Zr-TLX250 PET/CT Imaging ____________________________________________________ 55 
4.2.3 
Imaging Analysis _____________________________________________________________ 57 
4.3 
Treatment Assignment _________________________________________________ 57 
4.4 
Blinding _____________________________________________________________ 58 
4.5 
Treatment Compliance _________________________________________________ 58 
4.6 
Radiation Precautions __________________________________________________ 58 
4.7 
Total Radiation Exposure _______________________________________________ 59 
4.8 
Prior and Concomitant therapy___________________________________________ 59 
4.8.1 
Permitted concomitant therapy _________________________________________________ 59 
4.8.2 
Prohibited concomitant therapy _________________________________________________ 60 
5. 
STUDY DESIGN ______________________________________________________ 60 
5.1 
Overview of study design _______________________________________________ 60 
5.2 
Study design schedule __________________________________________________ 60 
6. 
STUDY PROCEDURES: DESCRIPTION AND SCHEDULE ________________________ 61 
6.1 
Screening visit ________________________________________________________ 61 
6.1.1 
Medical history ______________________________________________________________ 62 
6.1.2 
Physical examination and vital signs ______________________________________________ 62 
6.1.3 
Urine cytobacteriological testing ________________________________________________ 62 
6.1.4 
Laboratory evaluations ________________________________________________________ 62 
6.2 
Enrolment ___________________________________________________________ 63 
6.3 
89Zr-TLX250 PET/CT Imaging _____________________________________________ 64 
6.3.1 
89Zr-TLX250 administration _____________________________________________________ 64 
6.3.2 
89Zr-TLX250 PET/CT Imaging and Dosimetry________________________________________ 64 
6.4 
Follow-up visit: Day 30 following 89Zr-TLX250 administration___________________ 64 
6.5 
Study discontinuation __________________________________________________ 65 
7. 
SAFETY _____________________________________________________________ 66 
7.1 
Definitions ___________________________________________________________ 66 
7.1.1 
Adverse event Definition _______________________________________________________ 66 

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7.1.2 
Definition of serious adverse events _____________________________________________ 67 
7.1.3 
Expected adverse events _______________________________________________________ 67 
7.1.4 
Unexpected adverse events ____________________________________________________ 67 
7.1.5 
New Safety Issue _____________________________________________________________ 68 
7.2 
Investigator obligations _________________________________________________ 68 
7.2.1 
Adverse Events reporting ______________________________________________________ 68 
7.2.2 
Serious Adverse Events (SAEs) Reporting __________________________________________ 68 
7.3 
Sponsor obligations ____________________________________________________ 70 
7.3.1 
SAE Analysis _________________________________________________________________ 70 
7.3.2 
Relationship Scoring __________________________________________________________ 70 
7.3.3 
Notification of SUSARs to competent authorities ___________________________________ 71 
7.3.4 
Notification of New Safety Issue _________________________________________________ 71 
7.3.5 
Reporting of DSURs (Development Safety Update Report) ____________________________ 71 
7.3.6 
Reporting of other safety data __________________________________________________ 71 
7.3.7 
In utero exposure ____________________________________________________________ 72 
8. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION _________________ 73 
8.1 
Determination of sample size ____________________________________________ 73 
8.2 
Selection of patients to be included in the statistical analysis __________________ 73 
8.3 
Handling of missing, unused or invalid data_________________________________ 73 
8.4 
Description of analysis sets ______________________________________________ 73 
9. 
CONTROL AND QUALITY ASSURANCE ____________________________________ 74 
9.1 
Oversight Committees __________________________________________________ 74 
9.1.1 
Independent data monitoring committee _________________________________________ 74 
9.1.2 
Steering Executive Committee __________________________________________________ 74 
9.2 
Quality assurance _____________________________________________________ 74 
9.2.1 
Study monitoring _____________________________________________________________ 74 
9.2.2 
Monitoring Plan ______________________________________________________________ 75 
9.2.3 
Inspection / Audits ___________________________________________________________ 76 
10. 
ETHICAL AND REGULATORY CONSIDERATIONS ___________________________ 77 
10.1 
Clinical trial authorisation _______________________________________________ 77 
10.2 
Patient Information and Consent _________________________________________ 77 
10.3 
Sponsor responsibilities ________________________________________________ 77 
10.4 
Investigator responsibilities _____________________________________________ 78 
10.5 
Human biological samples collection ______________________________________ 79 
10.6 
Patient Committees ____________________________________________________ 79 
11. 
COLLECTION AND MANAGEMENT OF RESEARCH DATA ____________________ 80 
11.1 
Collection of study data_________________________________________________ 80 

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11.1.1 
Collection and conservation of study data _______________________________________ 80 
11.1.2 
Identification of all source data not contained in the patient medical file ______________ 80 
11.1.3 
Data coding _______________________________________________________________ 80 
11.2 
Study Data Processing __________________________________________________ 81 
11.2.1 
By the Sponsor ____________________________________________________________ 81 
11.2.2 
By sites, in the case of a computerised medical file is used _________________________ 81 
11.2.3 
Retention of documents _____________________________________________________ 82 
12. 
CONFIDENTIALITY AND OWNERSHIP OF DATA ___________________________ 83 
13. 
PUBLICATION AND VALORISATION RULES _______________________________ 84 
14. 
FINANCIAL ASPECTS ________________________________________________ 86 
15. 
LIST OF REFERENCES ________________________________________________ 87 
16. 
LIST OF APPENDIX __________________________________________________ 90 
 
 
 
 

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The study sponsor, the Institut de Cancérologie de l’Ouest (ICO), declares that the "PERTINENCE" 
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 
 
There is an unmet need for treatment of NMIBC. Currently the state of the art therapeutic options 
include BCG therapy and chemotherapy with mitomycine C. These therapies are efficient for some 
time but relapses repeat them at more and more close intervals and finally patients are refractory 
to them and require a radical cystectomy.  
Intravesical immunotherapy with BCG remains the standard of care for patients with high-risk and 
intermediate-risk non-muscle-invasive bladder cancer (NMIBC). Most patients initially respond, but 
recurrence is frequent and progression to invasive cancer is a concern. No established and effective 
intravesical therapies are available for patients whose tumors relapse after BCG, representing a 
clinically important unmet need. Development and discovery of treatment options for BCG-
unresponsive NMIBC is a high priority in order to decrease the morbidity, burden of health-care 
expenditures, and mortality related to bladder cancer. Alpha-immunotherapy is such a treatment 
option (1–4).   
Moreover these treatments have some uncomfortable side effects in a part of patients (flu-like 
symptoms, such as fever, achiness, chills, and fatigue. These can last for 2 to 3 days after treatment. 
It also commonly causes a burning feeling in the bladder, the need to urinate frequently, and even 
blood in the urine). 
 
The use of alpha-emitting radionuclides is a topical issue and of great interest to big pharmaceutical 
companies because of the high cytotoxic effect of alpha particles on tumor cells due to their high 
linear energy transfer and of the recognized good tolerance for healthy tissues due to the very short 
path length of alpha particle allowing to relatively spare normal tissue cells close to tumor cell 
clusters (5). 
 
The situation of non-muscle invasive bladder cancer corresponds well to radiophysical 
characteristics of alpha particles. Tumors have a small thickness corresponding well to the very 
short path length (<0.1 mm) of alpha particles and their superficial localization in the vesical cavity 
makes them accessible to a radiopharmaceutical intravesically instilled. Moreover the clinical 
situation of patients refractory to conventional treatment using BCG therapy or chemotherapy and 
for whom the only alternative is a radical cystectomy, justifies implementation of an innovative 
therapy like alpha- immunotherapy. The clinical proof of concept of such treatment has been 
provided by an academic German team at Munich University in 2018 (6). 
 
The preclinical study has been carried out in a mouse model by intravesical instillation of an anti-
EGFR (Epidermal Growth Factor Receptor) antibody labeled with bismuth-213, an alpha particle 

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emitting radionuclide with a half-life of 45 minutes (7). In this study, mice were intravesically 
inoculated with human bladder carcinoma cells after the induction of urothelial lesions by 
electrocautery. Mice were treated by intravesical instillation of non-labeled and labeled with 
bismuth-213 anti-EGFR Mab or of mitomycine C. Median survival of mice, not treated or treated 
with radiolabeled antibody was respectively of 41 and 89 days. In mice treated with 0.925 MBq of 
213Bi-anti-EGFR 7 days after inoculation of tumor cells, survival was more than 300 days in 80% of 
mice. In mice treated with mitomycine C 7 days after tumor cell inoculation, survival was more than 
300 days in 50% of mice but with a nephrotoxicity unlike treatment with 213Bi-anti-EGFR which 
showed no toxicity including the absence of macroscopic urothelial lesions. Finally this study 
documented the feasibility, efficacy and absence of toxicity of intravesical alpha-immunotherapy 
of bladder cancer. 
 
This preclinical study was followed by a clinical pilot study in 12 patients refractory to standard 
treatment and planned to undergo a radical cystectomy (6). An intravesical instillation of an activity 
of 366 to 821 MBq (10 to 22 mCi) of the 213Bi-anti-EGFR antibody was carried out in an empty 
bladder followed by 30 mL of PBS. Bladder was washed 120 min later. An excellent tolerability 
without any clinical of biological sign was observed in the 12 treated patients. Among the 12 treated 
patients, 3 who should have undergone a radical cystectomy, had a complete response which 
continued 3, 30 and 44 months after treatment. 
 
These two preclinical and clinical studies showed the feasibility, absence of toxicity and efficacy of 
intravesical alpha-immunotherapy. 
 
Intravesical instillation route has been chosen to limit the circulation of the radiopharmaceutical 
agent in the blood and to limit potential allergic immunoreactions with girentuximab which might 
occur by intravenous route. 
 
The main objective of this study is to prove that the 89Zr-Girentuximab is safe before developing a 
treatment for therapeutic purposes with girentuximab radiolabeled with a therapeutic 
radionuclide such as Astatine-211 (211At-Girentuximab). 
 
 
 
1.2 
Procedure Background 
1.2.1 
Girentuximab 
 
Immunohistochemical cross-reactivity studies were performed with girentuximab and a variety of 
normal human tissues (Internal report, Human tissue cross-reactivity study with human-mouse 
chimeric antibody cG250. Report dated 11.06.2001) and human tumor tissues (Internal Report 
Human tumor reactivity study with chimeric antibody cG250. Report dated 02.09.2002). The data 
confirm that the CAIX-antigen is widely expressed in ccRCC and absent from normal kidney tissue. 
Non-target tissues with significant CAIX-antigen expression were found to be foveolar parietal cells 
in the stomach, the epithelium of duodenum and the large bile ducts. 
 

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Alpha-immunotherapy requires an antibody, as a vector of a radionuclide through a coupling 
technology. This antibody is specific for an antigen which is expressed on the membrane of tumor 
cells. Among a substantial number of candidates the Carbonic Anhydrase IX (CAIX) has been shown 
to be expressed on the membrane of Non-Muscle-Invasive Bladder Cancer cells. CAIX expression 
was higher in noninvasive (Ta) versus invasive (T1-T4) tumors (P<0.001) in low-grade versus high-
grade bladder cancer (P<0.001) and in metastases versus the corresponding primary tumor 
(P<0.001) (8). The expression of CAIX on the luminal surface justifies investigation of its utility as a 
diagnostic/ therapeutic target/prognostic indicator (9). 
 
 
1.2.2 
89Zr-girentuximab 
1.2.2.1 
Structure 
 
 
 
Figure 1: Structure of 89Zr-girentuximab 
 
1.2.2.2 
Pharmaceutical development 
 
The drug product 89Zr-DFO-girentuximab (89Zr-TLX250 for intravenous administration), contains the 
radiometal 89Zr as a PET tracer agent at a dose of 37 MBq and is adjusted to a total antibody dose 
of 10 mg with unconjugated girentuximab in 0.9% NaCl.  
Girentuximab is a chimeric lgG1 monoclonal antibody specific for CAIX. CAIX is expressed 
abundantly in clear cell kidney carcinoma. The radiolabeled antibody (89Zr-girentuximab or 89Zr- 
TLX250) is developed for molecular imaging with PET. With this PET technique, it becomes possible 
to non-invasively image and quantify the uptake of girentuximab in kidney carcinomas.  
89Zr-TLX250 solution for intravenous administration consists of three major components (raw 
materials):  
A) No carrier added 89Zr, is a synthetic, metastable isotope of the radio metal Zirconium(atomic 
number 40) which decays first via positron emission and electron capture to 89mY (half-life of 
15.7s) which in turn decays via gamma ray emission (909 keV) to the stable 89Y (10). It emits 

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positrons with a main energy of 897 keV and an abundance of about 23%, thus providing high 
resolution PET imaging and good image quality. In addition, non-prompt 909 keV photons are 
emitted at an abundance of 99.9%. Nonclinical studies have shown that imaging and quantification 
of 89Zr by using a dedicated PET system is comparable with that of Indium-111 (111In), which is a 
widely used tracer (11). 
B)  Bifunctional chelate (DFP-TFP) The bifunctional chelator N-sucDf-TFP is the active TFP ester of 
the succinylated form of desferrioxamine (DFO), which is conjugated to girentuximab.  
C)  girentuximab (INN), or cG250. Girentuximab is an IgG1 kappa light chain chimeric version of the 
original murine monoclonal antibody in which human constant regions for the heavy and light 
chains have been linked by molecular DNA techniques to the corresponding murine variable heavy 
and light chain regions derived from the murine G250 antibody. The antibody is produced in a 
mouse myeloma cell line. It has a molecular weight of approximately 150 kD and is composed of 
two heavy and two light chains of relative molecular weight of 47 kD and 24 kD, respectively. 
girentuximab recognizes the surface antigen CAIX (alternative names: MN, CAIX-antigen) which is 
predominantly expressed on ccRCC. The unconjugated antibody is supplied as a clear, colourless to 
slightly brownish liquid.  
Girentuximab has been registered under the brand Rencarex® but has no marketing approval yet. 
124I-radiolabelled girentuximab has been investigated in several nonclinical and clinical studies. 
 
1.2.2.3 
Non clinical data  
 
1.3.2.3.1  
Unlabelled girentuximab 
 
Immunohistochemical cross-reactivity studies were performed with girentuximab and a variety of 
normal human tissues (Internal report, Human tissue cross-reactivity study with human-mouse 
chimeric antibody cG250. Report dated 11.06.2001) and human tumor tissues (Internal Report 
Human tumor reactivity study with chimeric antibody cG250. Report dated 02.09.2002). The data 
confirm that the CAIX-antigen is widely expressed in ccRCC and absent from normal kidney tissue. 
Non-target tissues with significant CAIX-antigen expression were found to be foveolar parietal cells 
in the stomach, the epithelium of duodenum and the large bile ducts.  
The anti-tumor effects of the murine or chimeric G250 antibody were studied in several 
experiments with nude mice xenografted with RCC (12) ; Internal Report Study P- 1103-008NIJ: 
Study for the demonstration of a protective and therapeutic effect of chimeric G250 (IgG1, cG250, 
synonym: girentuximab) and murine G250 (IgG2a, mG250) in NU/NU mice challenged with SK-RC-
52 cells; Report dated 29.03.2004). The murine antibody was used in these experiments due to 
poor interaction of girentuximab with murine effector cells. Repeated injections of the antibody 
significantly delayed the outgrowth of established tumors. This effect is assumed to be attributable 
to the induction of ADCC. In an in vitro experiment, girentuximab mediated potent ADCC against 
several RCC lines especially when effector cells had been stimulated with interleukin- 2 (13). 
 
1.3.2.3.2  
Radiolabelled 89Zr-girentuximab  
 

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89Zr-girentuximab imaging was investigated in three nonclinical studies, using rodent xenograft 
tumor models of ccRCC.  
Brouwers and colleagues (11) showed that conjugating girentuximab with the radionuclides 89Zr or 
111In allows high-contrast imaging of RCC tumors in RNU nude rats, already after 2 days. 3D PET 
imaging was performed at 5 minutes, 24, 48 and 72 hours after IV injection of 20 MBq 89Zr-
girentuximab, or of 4 MBq 111In-girentuximab. Comparative PET images after injection of 4 MBq 
[18F]FDG were recorded at 1 hour post-injection.  
Both, 89Zr-girentuximab and 111In-girentuximab, were stable during 4 days of incubation in serum 
and immunoreactivity was preserved. Biodistribution in normal tissues, uptake in tumor at 3 days 
post injection were almost identical between both radiolabelled girentuximab preparations (tumor 
uptake 5.0 ± 2.4 and 4.9 ± 2.9 %ID/g, respectively) (Figure 3). 
 
 
Figure 2: Biodistribution of [18F]FDG (n =7), 89Zr-girentuximab (n =8), and 111In- girentuximab (n 
=6) in nude rats with subcutaneous SK-RC-52 RCC tumors at 2 hours post injection [18F]FDG, or 72 
hours post injection (89Zr- girentuximab and 111In-girentuximab).  
 
Relatively small tumors of about 100 mg could be visualised from 24 hours post   injection of 89Zr- 
girentuximab. The quality of tumor imaging improved with time. In contrast, tumors were not 
visualized with [18F]FDG (uptake in tumor of 0.5 ± 0.1 %ID/g, 1 hour after injection).  
Blood levels at 3 days after injection were also identical (1.4 ± 0.4 versus 1.7 ± 0.7 %ID/g), and no 
significant differences were found in the biodistribution of normal tissues between the two 
radiolabelled girentuximab preparations.  
Both radiolabelled girentuximab preparations showed a relatively high uptake in liver, spleen and 
heart, resembling frequent sites of RCC metastases.  
Stillebroer et al. (14) recently reported a preclinical study in nude mice bearing cRCC tumors directly 
comparing 89Zr-girentuximab and 124I-girentuximab, showing differences in tracer uptake 
depending on the tumor model (SK-RC-52 or NU-12). Mice were injected with 89Zr-girentuximab 
(0.41 MBq/μg or 0.54 MBq/μg), or 124I-girentuximab (0.24 MBq/μg or 1.7 MBq/μg).  

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The group could show differences in tracer uptake depending on the tumor model. They observed 
significantly higher uptake of 89Zr-girentuximab compared with 124I-girentuximab.  
 
12 tumors (114.7%–25.2% injected dose per gram (%ID/g) vs. 38.2–18.3%ID/g, p=0.029), while 
there were insignificant differences in uptake between tracers in the SK-RC-52 tumor model (48.7– 
15.2%ID/g vs. 32.0–22.9%ID/g, p=0.26) (Figure 4). The higher specific uptake of 89Zr- girentuximab 
produced higher PET image contrast, despite higher uptake in various normal tissues, such as the 
liver and spleen.  
Intraperitoneal SK-RC-52 lesions as small as 7 mm3 were visualized with 89Zr-girentuximab PET. No 
information was reported on the size of lesions detected with 124I-girentuximab PET imaging.  
The authors hypothesized that labelling girentuximab with the residualizing positron emitter 89Zr 
would lead to higher tumor uptake and more sensitive detection of ccRCC lesions compared with 
124I. They concluded that small intraperitoneal ccRCC lesions could be visualized and easily 
discriminated from the liver and the spleen with girentuximab-based PET. 
 
 
 
 
Figure 3: Biodistribution of 89Zr-girentuximab and 124I-girentuximab in mice with a s.c. NU-12 
tumor (A) or a s.c. SK-RC-52 tumor (B), 7 days after injection. Values are expressed as mean–SD. 
Antibody protein dose was 3 μg girentuximab/mouse in NU-12 and 30 μg girentuximab/mouse in 

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SK-RC-52 tumors. Significant differences (p<0.05) in uptake between 89Zr- girentuximab and 124I-
girentuximab are marked with an asterisk* 
 
Cheal and colleagues (15) conducted a quantitative comparison of absolute uptake and antibody 
turnover between 124I-girentuximab and 89Zr-girentuximab using a human cRCC xenograft tumor 
model (SK-RC-38) in female nude mice. The mice were injected IV with 89Zr-girentuximab (14.6 to 
15.0 MBq, 40 μg, 267 pmol) or 124I-girentuximab (11.8–12.6 MBq, 100 μg, 667 pmol) and were 
serially imaged by PET over the course of 10-11 days to determine the kinetics of the tracer uptake 
in the tumor and the rate of clearance from the vascular department.  
The stability of 89Zr-girentuximab in human serum was evaluated in vitro over 11 days at 37°C by 
ITLC, showing that ≥ 97.8% of the total 89Zr activity remained in a form consistent with 89Zr- 
girentuximab over the course of the study. For comparison, the stability of 124I-girentuximab in 
human serum was > 99% of the total 124I-activity, consistent with intact protein (i.e. 124I-
girentuximab).  
Tumor activity concentrations were expressed as the maximum %ID/g in manually drawn two- 
dimensional tumor-contouring regions of interest (ROIs). While both tracers allowed for high- 
contrast imaging of RCC, the comparative intra-tumoral concentrations varied significantly from 5 
hours to 10 days after injection. This observation could not be explained by differences in clearance, 
as the biological half-lives as determined by quantitation of activity in circulation were not 
significantly different (Figure 5).  
 
 
 
 
Figure 4: Time-activity curves for 124I- or 89Zr-girentuximab uptake (over tumor ROIs) in SK-RC-38 
xenografts (n = 5 for each cohort) up to 10 and 11 days post injection, respectively. Data are 
expressed as (mean ± standard error of the mean (SEM)). 
 
Biodistribution studies for 124I-girentuximab and 89Zr-girentuximab were performed 10 and 11 
days after the injection, respectively (Figure 6). 
 
The concentration of the tracer in the target tumor tissue was by far highest for 89Zr-girentuximab 
compared with the tumor activity of the non-residualizing 124I-girentuximab (40 %ID/g for 89Zr and 
5 %ID/g for 124I).  

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Higher concentrations of 89Zr-girentuximab than 124I-girentuximab were found in liver (p < 0.05), 
spleen, kidney, and bone (all p < 0.005), presumably due to the metabolism and hepatobiliary 
clearance of radiometal complexes in catabolic organs such as liver and kidneys, and the affinity of 
the phosphate-rich bone for free 89Zr (16).  
While non-specific tracer uptake in normal tissue, especially in the liver and bone, potentially might 
mask metastatic disease in these organs, the observed tumor-to-background ratio, relative to these 
organs would still allow identification of such lesions. 
 
 
 
Figure 5: Comparative biodistribution data for 89Zr-girentuximab and 124I- girentuximab following 
serial PET imaging (11 days for 89Zr-girentuximab and 10 days for 124I-girentuximab). Groups 
consisted of 4 or 5 mice each. Data for 124I- girentuximab is from group of animals with normal 
thyroid attime of tracer injection. The data are expressed as mean %ID/g ± SEM. (*) p < 0.05, (**) p 
< 0.005. 
 
 
89Zr- and 124I-girentuximab were virtually identical in terms of clearance from the blood, Initial 
tumor binding and uptake within 5 hours, and rate of internalization of the girentuximab-CAIX 
antibody- receptor complex. However, notable differences in tumor uptake over time and 
retention of the tracer existed. Uptake of 89Zr-girentuximab further increased from 48 hours post 
injection to a plateau of about 20 %ID/g, which persisted to the last imaging time point at 11 days 
post injection. The peak uptake of 124I-girentuximab was much lower (at about 5 %ID/g) and was 
observed already at 5–24 hours, with subsequent washout to about 2 %ID/g at 10 days after 
injection (Figure 7). 
 
In vivo kinetic models yielded estimates of internalization of the receptor-bound antibody of 20 
%ID/g/h, with minimal release of 89Zr but with comparable uptake of 124I-girentuximab leading to 
release of considerable amounts of 124I. The 124I atoms were cleared from tumor more than 17.5 
times more rapidly than 89Zr. 
 

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Figure 6: Comparative serial-PET imaging in tumor-bearing mice using 89Zr- girentuximab and 124I-
girentuximab at various time points up to 11 days post injection. Representative transverse (trans.) 
and coronal PET images of nude mice bearing subcutaneous SK-RC-38 xenografts in the lower hind 
limb imaged with 124I- or 89Zr-girentuximab at various time points up to 11 days post injection. 
Arrows indicate position of tumor. Images are parameterized as %ID/g. 
 
1.2.2.4 
Conclusions  
 
The long-lived radiometal 89Zr has emerged as an attractive alternative to 124I, owing to its 
residualizing properties in vivo. The above described studies demonstrate, that the residualizing 
radionuclide 89Zr is well suited to image the girentuximab/CAIX biology. In all nonclinical studies, 
89Zr-girentuximab PET imaging was superior compared to 124I-girentuximab PET imaging, because 
of prolonged trapping of the radiolabel in the tumor, while at the same time showing washout from 
normal tissues. Antibody-based molecular imaging with internalizing and residualizing 
radionuclides such as 89Zr PET or 111In SPECT imaging in rodent studies, demonstrated that the 
quality of tumor imaging improved with time, due to the washout of the background. This is a clear 
advantage over non-internalizing and non-residualizing tracers such as 124I, which has a > 17 times 
higher leakage rate form tumor after internalization. 
 
1.2.2.5 
Pharmacokinetics and Product Metabolism in Animals  
 

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Binding characteristics of girentuximab are of primary relevance for its pharmacokinetic 
characteristics as a potential medical drug. Girentuximab binds to the extracellular domain of 
human CAIX and is cross-reactive with the primate and rabbit homologues of CAIX.  
Pharmacokinetic studies were conducted in rabbit and Rhesus monkey (Macaca mulatta). Studies 
in rabbits were conducted with 131I- and 125I-labelled girentuximab. For pharmacokinetics studies 
antigen cross-reactivity and similarity of tissue-specific antigen expression pattern (as is given in 
both species), but not necessarily Fc receptor interaction, are prerequisite to qualify an animal 
model for this type of studies.  
The immunogenicity of girentuximab (frequency and degree of induction of antibodies to 
girentuximab, i.e. Rhesus anti-chimeric antibody, RhACA) was characterized in the course of toxicity 
studies in Rhesus monkey. 
 
1.2.2.5.1 
Single-Dose Pharmacokinetics and Elimination of Girentuximab in Rabbits  
 
The pharmacokinetics and elimination of girentuximab following single intravenous administration 
were studied using 125I or 131I-labelled girentuximab. A non-primate animal model i.e. rabbit was 
chosen for the single-dose pharmacokinetic studies of radiolabelled girentuximab. The approach in 
rabbit was justified by the cross-reactivity of girentuximab shown with the rabbit CAIX-antigen 
(G250 binding site) and a similar tissue-specific antigen expression pattern in rabbit compared to 
man.  
In three pharmacokinetic rabbit studies (Internal Reports 01-50015, 01-50022, and 01-50031) two 
girentuximab lots radiolabelled with 125I or 131I were mixed and simultaneously administered 
intravenously at two different dose levels of 50 and 500 μg/kg per lot. The combined total 
girentuximab dose was therefore 100 μg/kg and 1000 μg/kg. The elimination of the radiolabels was 
differentially tracked in whole blood samples taken at various time points after injection over 48 
hours. The rabbits were sacrificed 48 hours after injection and tissue samples of liver, kidney, 
spleen, pancreas, duodenum, stomach, muscle, and colon were collected, weighed and the amount 
of radioactivity of each isotope was determined in a gamma counter for comparative girentuximab 
tissue distribution analysis.  
Terminal half-life, t1/2ß was apparently dose-dependent with 17 to 19 hours for the low and 25 to 
32 hours for the high antibody dose. At 48 hours after administration to the rabbits, highest levels 
of radioactivity were evident in the duodenum, followed by colon, liver, and stomach. This ranking 
of girentuximab binding to organs was consistent in all three rabbit studies and is in line with the 
binding to human nontarget tissues. Girentuximab specifically binds to CAIX expressed on the 
surface of these tissues. 
A pharmacokinetic two compartment model was found to be optimal to describe the blood 
elimination curve of girentuximab in rabbit (Table 2). The same model is optimal in humans and 
monkeys. 
 
 

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Table 2: Elimination of girentuximab Following a Single Intravenous Administration in Rabbits 
 
Study No  
01-50015 
01-50022 
 
01-50031 
Sex / Number of 
animals  
F / 18  
 
F / 18  
 
F / 18  
Analyte  
cG250-CEN and cG250-
AVID, both 125I- and 131I-
radiolabelled  
cG250-WI and cG250- 
FLA, both 125I- and 131I- 
radiolabelled  
cG250-AVID-WI and 
cG250-AVID-FLA, both 
125I- 
and 131I- radiolabelled  
Assay  
gamma counting of 
125I- 
and 131I- radiolabelled 
compound  
gamma counting of 
125I- 
and 131I- radiolabelled 
compound  
gamma counting of 
125I- and 
131I- radiolabelled 
compound  
PK parameters in 
(whole blood):  
50 μg/kg  
500 μg/kg  
50 μg/kg  
 
500 μg/kg  
 
50 μg/kg  
500 μg/kg  
T1/2α [h] (lot A; lot 
B)  
2.2; 2.0  
 
2.4; 2.2  
1.9: 1.7  
3.0; 2.7  
0.7; 0.7  
0.9; 0.8  
T1/2ß [h] (lot A; lot 
B)  
17.1; 17.1  25.5; 25.1  
19.0; 18.7  32.4; 31.6  18.7; 18.5  
25.8; 25.4  
PK parameters1 
(serum):  
100 μg/kg   
1000 μg/kg  
100 μg/kg  1000 μg/kg  100 μg/kg  
1000 μg/kg  
AUC0-∞ (μg/mL*h)  49.6  
947.6  
67.4  
960.8  
59.3  
795.6  
T1/2 ß (h)  
16.8  
23.7  
18.6  
30.9  
18.7  
25.1  
Cmax (μg/mL)  
2.9  
 
36.7  
3.3  
31.3  
2.6  
24.7  
 
1 To create comparability with PK studies in human whole blood concentration data generated in 
the three rabbit studies were converted into serum concentrations. Because the production lot 
comparison revealed comparable elimination profiles for the different production lots in all three 
experiments, serum PK parameter modelling for girentuximab was done based on mean combined 
serum concentration data of both lots in each study. 
 
The dose-dependent elimination half-life of girentuximab observed in the three rabbit-single-dose 
studies may be explained by the contribution of a saturable elimination pathway to overall 
elimination kinetics such as target binding and internalization. Dose-dependent elimination kinetics 

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of girentuximab was also described in humans (17) where a 2-mg dose eliminated faster than higher 
doses ranging from 5 to 50 mg. Dose-dependent elimination half-life was also seen in the Rhesus 
monkey 6-month toxicity study, where the low dose of 1.5 mg/kg eliminated with a significantly 
shorter terminal half-life compared with the two higher doses (5 and 15 mg/kg) (Internal Report 
01-14005).  
In the three in vivo biodistribution studies in rabbits strong binding of radioactive girentuximab to 
the duodenum was found. Positive duodenal expression of the CAIX-antigen corroborates the 
suitability of rabbit as model for the pharmacokinetics of radiolabelled girentuximab. 
 
1.2.2.5.2 
Repeat-Dose Pharmacokinetics of Girentuximab in Rhesus Monkeys  
 
The therapeutic use of girentuximab as an adjuvant treatment of ccRCC involves a single loading 
dose of 50 mg and subsequent maintenance doses of 20 mg administered once weekly over 6 
months. Repeat-dose pharmaco-/toxicokinetic data were derived from pivotal toxicological 
primate studies. In particular, the girentuximab serum kinetics studies accompanying the 3-month 
and 6- month toxicity studies (Internal Reports 01-13001 and 01-13006) as well as a 4-week toxicity 
study in Macaca mulatta (Rhesus monkey) are described herein.  
Pharmacokinetic parameters (Cmax, AUC0-∞ and t1/2β) of girentuximab were determined from 
the plasma concentration profiles obtained during Week 1 of a 12-week toxicity study in Rhesus 
monkey.  
A two-compartment model best describes the pharmacokinetic plasma profile in monkeys. The 
same applies for human pharmacokinetics of girentuximab.  
T1/2β values are within a comparable range in both species (mean t1/2β human: 176 hours (± 73 
hours); mean t1/2β monkeys: 142 hours (± 41 hours).  
These pharmacokinetic features of girentuximab in Rhesus monkey were confirmed in a 6-month 
chronic toxicity study with three girentuximab dose levels of 1.5, 5 and 15 mg/kg. Mean terminal 
half-lives determined in the 6-month chronic toxicity study in Rhesus monkeys were similar for 
males and females, but showed some dose-dependence, i.e. a prolongation with dose, as was 
observed in the rabbit model. Shorter elimination half-lives were observed in the low dose groups 
receiving girentuximab at 1.5 mg/kg compared with the two higher dose groups. Elimination half-
lives, however, were similar in the medium and the high dose group. Shorter elimination half-lives 
of girentuximab at lower doses may be explained by the contribution to overall elimination of a 
saturable receptor-mediated pathway via binding to the CAIX-antigen followed by internalization, 
while at higher doses non-saturable pathways e.g. nonspecific clearance by the RES predominate. 
In line with the long serum half-life of girentuximab the antibody showed some accumulation in 
serum after weekly repeated administrations. Once steady state had been achieved after ≤ 6 
weeks, however, no further accumulation of girentuximab occurred during the course of the study. 
This limited accumulation of girentuximab in serum was not associated with signs of toxicity 
throughout the study.  
Consequently, the pharmacokinetic profile of girentuximab in Rhesus monkeys and humans 
appears to be similar.  
The formation of Rhesus monkey-RhACA was measured following the sporadic observation of 
human anti chimeric antibodies (HACAs) in clinical trials. RhACA formation started after repeated 

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administration of the antibody, but was not associated with clinical symptoms or changes in 
laboratory parameters 
 
1.2.2.5.3 
Product Metabolism  
 
Studies on drug metabolism are inappropriate for protein drugs such as an antibody and no such 
studies have been conducted with girentuximab.  
The metabolism of proteins, such as antibodies, is well known and can be confined to (i) ubiquitous 
enzymatic digestion to peptides and amino acids and (ii) modifications to this pathway in the case 
of ligand-receptor interactions or complex formation between antibody and surface antigen, if 
therapeutic protein binding is followed by endocytosis and intracellular degradation of the 
complex. Ubiquitous proteases are not likely to undergo pharmacologically relevant induction or 
inhibition.  
 
1.2.2.5.4 
Elimination  
 
Following enzymatic digestion of antibodies to antibody fragments, peptides, amino acids, 
carbohydrates, CO2 and NO2, the degradation products enter the major intermediate metabolic 
cycles, esp. in the hepatobiliary system, and/or are excreted with the urine or the faeces or exhaled.  
Most of the radioactivity of the radiometal 89Zr will be excreted in faeces as it is hepatically cleared 
together with girentuximab during the first few days (approx. 5 days) after the infusion, but very 
small amounts may also be eliminated via saliva, sweat and urine.  
 
1.2.2.5.5 
Toxicology  
 
No particular studies on safety pharmacology were conducted with the naked girentuximab, the 
124I- or the 89Zr-girentuximab.  
No single dose toxicity study has been conducted. Information on (i.e. the absence of) single dose 
toxicity may, however, be derived from multiple administration studies. Acute reactions to 
girentuximab were investigated in the repeat-dose toxicity studies as well as the relationship of 
dose to systemic or local toxicity. No additional information was expected to be gathered from 
single dose administration of the antibody in non-human species. 
 
1.2.2.5.5.1 Girentuximab  
 
Repeated dose toxicity studies for 30 days, 12 weeks and 6 months with doses administered once 
weekly were conducted in Macaca mulatta (Rhesus monkey): 6-month toxicity study of 
girentuximab after repeated slow bolus injection to Rhesus monkeys. Report dated 22 Sep 2008) 
Monkeys express cross-reactive CAIX antigen in a manner similar to humans, provide an 

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immunological environment reactive with the constant portions of the antibody and are therefore 
a suitable model for toxicity studies. The doses per body weight in the repeat dose monkey studies 
were several-fold higher than the proposed human doses in immunotherapy trials and produced 
exposures several-fold higher than in the human therapeutic setting. Girentuximab was well 
tolerated in the monkey studies and no relevant toxicity was observed. The safety in monkeys of 
chronic exposure at multi-fold higher levels than intended for imaging suggests safety of the single 
dose administration of radiolabelled girentuximab for imaging.  
 
1.2.2.5.5.1 
89Zr-girentuximab  
 
In nonclinical rodent studies, imaging using 89Zr-girentuximab has proven to be safe and feasible 
(11,14,15). No local or systemic side effects were observed. 
 
1.2.3 
Effects in Humans  
 
Imaging with radiolabelled girentuximab can lead to an accurate identification of ccRCC, or provide 
information to rule out ccRCC, and thus offers opportunities for less aggressive patient 
management.  
Table 3: Clinical Studies in Patients with Unlabelled girentuximab – Dose Regimen, Mean Steady-
state Trough Levels, Clinical Benefit, Incidence of HACA Formation and Safety Profile 
Trial code  
WX-2000-01-NAK  
(Monotherapy)  
WX-2000-04-GIL  
(Combination therapy 
with IL-2)  
 
WX-2001-05-IFN  
(Combination 
therapy with IFN-
α)  
WX-2003-07-HR  
(Monotherapy)  
Design  
An open label single 
arm phase 2 study of 
girentuximab 
administered weekly 
by IV infusion to 
advanced renal cell 
carcinoma patients  
A phase 1/2 study 
with girentuximab and 
low dose IL-2 plus 
periodic IL-2 pulsing 
in advanced and 
metastatic renal cell 
carcinoma patients  
A phase 1/2 study 
with girentuximab 
and IFNα-2a in 
metastatic renal 
cell carcinoma 
patients  
A randomized, double 
blind, phase 3 study to 
evaluate adjuvant 
girentuximab treatment 
versus placebo in 
patients with clear cell 
RCC and high risk of 
recurrence  
Clinical Phase  
2  
1/2  
 
1/2  
3  
Patient Exposure 
(total of 545 
patients, incl. 
patients from 
LUD 98-011)  
36  
36 Caucasian 
12 female, 24 male  
35 
34 Caucasian  
1 Asian 
8 female, 27 male  
31  
31 Caucasian 
8 female, 23 male  
 
431 
403 Caucasian  
10 Asian 
10 African 
8 Hispanic 
156 female, 275 male  
Girentuximab 
dose regimen  
50 mg once weekly for 
12 weeks  
20 mg once weekly 
for 11 weeks  
20 mg once 
weekly for 11 
weeks  
Single loading dose of 
50 mg (Week 1) followed 
by weekly infusions of 

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20 mg of girentuximab or 
placebo over 24 weeks  
Girentuximab 
plasma trough 
level (mean 
value)  
15.9 μg/mL  
4.7 μg/mL  
 
6.7 μg/mL  
≥8.7 μg/mL (from Week 
8 on)  
Clinical Benefit 
Rate* (Evaluated 
patients/ITT)  
28% (9/32) 25% (9/36) 23% (7/30) 20% 
(7/35)  
41% (11/26) 
35.48% (11/31)  
Not applicable  
Incidence of 
HACA 
formation** (%)  
2 out of 36 (5.6%) no 
clinical symptoms  
2 out of 35 (5.7%) no 
clinical symptoms  
None out of 31 
(0%)  
51 patients out of 431** 
(11.8%) 
37 patients out of  
431*** (8.6%) with 
neutralising HACAs  
Safety profile  
• 13 SAEs, not 
treatment-related • 
147 Non-Serious  
• 4 SAEs, not 
treatment-related • 
420 Non-Serious  
• 6 SAEs, not 
treatment-related • 
183 Non-Serious  
• 72 SAEs, only 1 
treatment-related 
(placebo)  
 
* Clinical Benefit Rate defined as Response rates (CR and PR) plus Stable Disease ≥ 24 weeks **Any 
HACA regardless of neutralising or non-neutralising properties 
*** Number of patients in the active treatment arm 
 
1.2.3.1 
Pharmacokinetics and Product Metabolism in Humans 
 
The pharmacokinetics (PK) of intravenous girentuximab is best described using a two- 
compartment pharmacokinetic model with first-order elimination. The serum exposure to 
girentuximab is dose linear and dose proportional within the dose range 5 to 100 mg. The terminal 
serum elimination half- life is independent of dose within this range. A 2-mg dose produces 
disproportional low exposure and is eliminated with a faster serum half-life compared with higher 
doses. Doses of 10 mg or higher produce Cmin (trough) serum levels above 1 μg/mL one week after 
the dose. Girentuximab concentrations of 1 μg/mL reproducibly elicited ADCC in vitro. Thus, 20 mg 
girentuximab administered once weekly is suitable to warrant sufficient and sustained antibody 
concentrations adequate at inducing ADCC.  
Continuous treatment with 20 mg girentuximab once a week over several months produces a mean 
serum concentration of approximately 9 μg/mL at steady state. This steady state is achieved 
between Week 4 and Week 8 and exceeds multi-fold the minimal concentration of 1 μg/mL which 
is adequate to elicit ADCC in-vitro.  
Elimination parameters are similar comparing single dose and multiple dose elimination kinetics. 
Mean parameters registered in tumor-bearing renal cancer patients were approximately 19 ± 7 h 
for t1/2α, 180 ± 87 h for t1/2ß, 22 ± 10 mL/h for the clearance, 3.1 ± 0.7 L for the central volume 
of distribution and 4.6 ± 1.3 L for the volume of distribution at steady state. Exposure parameters 
AUC and Cmax are largely linearly correlated with the dose. Mean AUCinf values of 123 ± 46 
μg*h/mL, 1671 ± 572 μg*h/mL, 2643 ± 462 μg*h/mL and 4519 ± 254 μg*h/mL were noted after 
infusion of girentuximab at relative doses of 5, 10, 25 and 50 mg/m2. Mean Cmax levels of 3.1 ± 

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0.2 μg/mL, 8.0 ± 1.2 μg/mL, 17.6 ± 4.3 μg/mL and 30.9 ± 3.6 μg/mL were noted at the four dose 
levels assayed.  
A population pharmacokinetic study considering elimination profiles sourced from seven clinical 
studies was conducted to identify covariates influencing the pharmacokinetics of girentuximab. 
Age, gender, aspartate aminotransferase (AST), creatinine clearance (CRCL) and total bilirubin 
(TBIL) are not statistically significant predictors of clearance and the central volume of distribution. 
Furthermore, age, body weight, BSA, BMI, ideal body weight, AST, CRCL, and TBIL are not 
statistically significant predictors of the peripheral volume of distribution. The presence of the 
primary renal tumor in a patient increases the volume of distribution approximately 4-fold 
compared with healthy volunteers or nephrectomised renal cancer patients. The serum clearance, 
however, was not significantly influenced by the presence of tumor.  
Pharmacokinetic analysis was performed with unlabelled girentuximab in main study WX-2007- 10- 
HV and with 131I-girentuximab in main study LUD 98-011. Results will be supported by 
pharmacokinetic data from historical studies with 131I-girentuximab.  
In Study WX-2007-10-HV a single IV dose of unlabelled girentuximab was administered to healthy 
volunteers.  
Study LUD 98-011 administered six weekly IV infusions of girentuximab at doses of 5, 10, 25, or 50 
mg/m2 to patients with advanced RCC. The first and fifth doses of girentuximab were trace labelled 
with 131I (8-10 mCi).  
A comparison of the pharmacokinetics in these two studies is provided in Table 5. 
 
1.2.3.1.1 
Phase 1 Study: Single Dose intravenous administration of 20 mg 
girentuximab in Healthy Volunteers (Study WX-2007-10-HV) 
 
The objective of the study was the determination of individual pharmacokinetic parameters and 
parameter ranges of girentuximab plasma elimination profiles observed in 12 healthy volunteers 
of both sexes after a single intravenous dose of 20 mg girentuximab. For each individual profile 
non- compartmental, two compartmental or three compartmental pharmacokinetic modelling was 
applied. The two-compartment model was found to fit measured profiles best. Concentration-time 
profiles of all healthy volunteers are shown in Figure 8. Serum concentration-time profiles of the 
study population showed a uniform and consistent shape during the initial and the terminal phase 
of elimination. 
 

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Figure 7: Pharmacokinetics of unlabelled girentuximab in Healthy Volunteers 
 
At the 336-hour sampling time, quantifiable data were obtained from six volunteers. For the other 
six volunteers girentuximab concentrations were found to be below the limit of quantification. For 
these six volunteers the last sample considered for parameter calculation was the one taken at the 
sampling time point 168 hours. At the end of the pharmacokinetic sampling period (504 hours after 
start of infusion, data not shown) girentuximab concentrations were below the limit of 
quantification for all volunteers.  
The two-compartment model was determined to be optimal for determination of the 
pharmacokinetic parameters of these healthy volunteers. A two-compartment model, as a bi- 
exponential model, generates two half-lives, the alpha (t1/2α) and beta (t1/2β) half-life. The alpha 
half-life is the distribution half-life, and the beta half-life is the overall elimination half-life in the 
terminal phase. t1/2α had a wide range (2.2 – 32 hours) with a mean of 15.1 hours (standard 
deviation [SD] of 11.5 hours). T1/2ß ranged from 91 to 269 hours with a mean of 176.4 hours (SD 
of 72.5 hours).  
During steady-state there is equilibrium of the concentrations in all compartments with no net 
transport between them.  
The serum profiles and PK parameters suggest little inter-individual variability, hence good 
predictability of exposure. Also, these data suggest no major influence of gender on girentuximab 
profiles. The serum Cmax values achieved have a narrow distribution around the population mean 
with a coefficient of variation (CV) of 26.3%. The mean terminal serum half-life (t1/2β) in this 
healthy volunteer population was approximately one week. This is similar to the mean terminal 
serum half- life reported for pre-surgery kidney cancer patients bearing their primary tumor in a 
study with 131I- girentuximab (t1/2α of 19.0±6.8 h and t1/2ß of 180.2±86.9 h) (Study LUD 98/011). 
The pharmacokinetics of girentuximab in healthy volunteers, is also similar to the pharmacokinetics 
reported in a population of nephrectomised metastatic ccRCC patients (11). 
 
 

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1.2.3.1.2 
Phase 1 Study: Multiple-dose, Dose Escalation Study of Girentuximab in 
Patients with Advanced Renal Cell Carcinoma (Protocol LUD 98-011) 
 
Study LUD 98-011 was a phase 1, open-label, non-randomized, dose escalation study designed to 
evaluate the safety of escalating doses of girentuximab administered IV once weekly for 6 weeks 
to patients with advanced RCC. Secondary objectives included determination of blood 
pharmacokinetics, organ and tumor distribution of girentuximab, and evaluation of immune 
response and anti-tumor effects.  
A total of 13 eligible male and female patients, 46-73 years of age, were enrolled.  
Four dose groups received weekly IV infusions of girentuximab for 6 weeks at one of four doses (5, 
10, 25, or 50 mg/m2). Three to four patients were treated per dose level. The first and fifth infusions 
at each dose level were trace-labelled with 8-10 mCi of 131I for the evaluation of biodistribution and 
other parameters. All patients showed 131I-girentuximab tumor localisation by gamma camera 
imaging in Weeks 1 and 5.   
  
Pharmacokinetics  
During Weeks 1 and 5, blood samples were collected for pharmacokinetic analysis immediately 
prior to the 131I trace-labelled study treatment infusion, 10 minutes, and 1, 2, and 4 hours after 
completion of the infusion. Samples for determination of radioactivity were also obtained on Day 
1, on Day 2 or 3, on Day 4 or 5, and Day 6 or 7, in conjunction with gamma camera imaging.  
Blood samples were collected in Weeks 1 through 6 immediately prior to infusion and 10 minutes 
following completion of infusion. In addition, a blood sample was collected in Week 8. 
Pharmacokinetic analyses were performed by measurement of serum 131I radioactivity and by ELISA 
assay of serum girentuximab. Thirteen patients were evaluable for pharmacokinetics.  
Pharmacokinetic parameters from the first cycle of treatment (Week 1 and Week 5 infusions of 
131I- labelled girentuximab as a pharmacokinetic probe) are presented in Table 4. Repeated 
intravenous doses of up to 50 mg/m2 of girentuximab were safe using once a week administration. 
There was no change in PK on repeated dosing and accumulation was low.  
 
 
 
 
 
 
 
 
 
 

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Table 4: Pharmacokinetic Parameters of 131I-girentuximab Following Multiple Dose Administration 
in Patients with RCC (Study LUD 98-011) 
Parameter, mean ± 
SD1  
girentuximab Dose (mg/m2)  
5 (N=3)  
10 (N=3)  
25 (N=4)  
50 (N=3)  
All (N=13)  
t1/2α (h)  
21.3 ± 5.41  
25.3 ± 3.39  
 
17.9 ± 6.73  
 
11.8 ± 4.93  
19.0 ± 6.84  
t1/2β (h)  
122.9 ± 45.68  272.3 ± 114.55  184.9 ± 72.51  139.1 ± 41.94  180.2 ± 86.68  
AUC (h·μg/mL)  
309.9 ± 77.99  1671 ± 571.98  2643.2 ± 
462.34  
4519.3 ± 
253.9  
 
NA  
Cmax (μg/mL)2  
3.1 ± 0.21  
8.0 ± 1.17  
17.7 ± 4.29  
30.9 ± 3.56  
NA  
CL (mL/h)  
33.8 ± 15.98  16.7 ± 7.60  
19.0 ± 4.72  
21.6 ± 4.52  
 
22.5 ± 10.28  
MRT (h)  
153.3 ± 51.6  360.3 ± 147.12  248.9 ± 96.73  193.6 ± 52.93  239.8 ± 113.66  
V1 (mL)  
3149.9 ± 
741.48  
3206.1 ± 
1103.90  
2887.0 ± 
895.91  
3141.0 ± 
441.93  
 
3079.9 ± 
739.24  
Vss (mL)  
4626.8 ± 
240.93  
5376.0 ± 
2031.87  
4542.4 ± 
1708.3  
4087.5 ± 
906.65  
4649.3 ± 
1333.88  
 
1 Mean of Week 1 and Week 5 infusions  
2 131I-labelled-girentuximab assay  
Abbreviations: AUC: area under the concentration curve extrapolated to infinite time; Cmax: 
maximum serum concentration; CL: total serum clearance; MRT: mean serum residence time; NA: 
Not Applicable; SD: standard deviation; T1/2α and T1/2β: half-lives of the initial and termination 
phases of disposition, respectively. V1: volume of central compartment; Vss: volume of distribution 
at steady state.  
No statistical differences were shown between dose levels for the mean (± SD) values of T1/2α, 
T1/2β, CL (total serum clearance) or MRT (mean serum residence time) for 131I-labelled 
girentuximab (ANOVA, p > 0.112).  
The V1 (volume of central compartment) and Vss (volume of distribution at steady state) results 
also showed no differences between protein dose levels and were consistent with a two- 
compartment model for pharmacokinetic analysis.  

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The Cmax and AUC values showed a linear relationship to dose of girentuximab.  
The 89Zr-girentuximab to be used as an imaging agent will be administered as a single dose; 
however, of note, infusions of girentuximab within a cycle were associated with increasing values 
for Cmax and Cmin.  
1.2.3.1.3 
Comparison of Pharmacokinetics in Study WX-2007-10-HV and Study LUD 
98-011  
 
The pharmacokinetic measurements determined from the two studies in healthy volunteers and in 
patients with RCC are compared in Table 5.  
Despite the study population and dosing differences, the pharmacokinetics of unlabelled and 131I- 
radiolabelled girentuximab were similar between the two clinical studies. A two-compartment 
model appears to be appropriate for pharmacokinetic analysis of girentuximab, irrespective of 
radiolabel or disease state.  
 
Table 5: Pharmacokinetic Parameters of Naked girentuximab in Healthy Volunteers Compared with 
131I-girentuximab in Patients with RCC (Studies WX-2007-10- HV and LUD 98-011) 
Parameter, mean 
± SD1  
 
Study WX-2007-10-HV 20 mg 
girentuximab in Healthy Volunteers  
 
Study LUD 98-011  
25 mg/m2 131I-girentuximab in 
Patients with RCC  
(N=12)  
25 (N=4)  
t1/2α (h)  
15.1 ± 11.5  
17.9 ± 6.73  
t1/2β (h)  
176.4 ± 72.5  
184.9 ± 72.51  
AUC (h·μg/mL)  
1202.3 ± 448.1  
2643.2 ± 462.34  
Cmax (μg/mL)  
7.7 ± 2.0  
17.7 ± 4.29  
CL (mL/h)  
17.9 ± 6.4  
19.0 ± 4.72  
Vss (L)  
3.9 ± 1.1  
4.5 ± 1.7  
 
1 For Study LUD 98-011, mean of Week 1 and Week 5 infusions;  
Abbreviations: AUC: area under the concentration curve extrapolated to infinite time; Cmax: 
maximum serum concentration; CL: total serum clearance; NA: Not Applicable; SD: standard 
deviation; t1/2α and t1/2β: half-lives of the initial and terminal phases of serum elimination, 
respectively. Vss: volume of distribution at steady state  
 
Compared with studies WX-2007-10-HV and LUD 98-011, shorter t1/2α and t1/2β values were 
observed in a previous clinical study performed in patients bearing the primary RCC (Steffens, 
1997). The discrepancy in terminal serum half-life between the studies may relate to the 
sequestration of girentuximab from serum by binding to the primary tumor present in the patients 
investigated by Steffens et al. The concentration of residual serum girentuximab one week after 

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the dose (C168 h) may therefore be expected to be lower in kidney cancer-bearing patients than 
suggested by data generated in the healthy volunteer population (WX-2007-10-HV) or in a 
population of nephrectomized metastatic ccRCC patients (Study LUD 98-011).  
Pharmacokinetics of 124I-girentuximab or 89Zr-girentuximab are not anticipated to be substantially 
different from those of girentuximab and 131I-girentuximab.  
With girentuximab having a terminal half-life of approximately one week and 89Zr having a decay 
half-life of approximately 3.3 days, 89Zr-girentuximab provides good visualization on PET/CT images 
following clearance of background radiolabel from the sera. 
 
1.2.3.2 
Safety and Efficacy  
 
1.2.3.2.1 
Girentuximab  
 
There is ample experience with radiolabelled tumor targeting in patients using the anti-CAIX 
antibody girentuximab. Although never observed in previous trials, allergic-type reactions are 
possible during and immediately following the administration of girentuximab.  
As of November 2017, 545 patients have been treated with unconjugated girentuximab 
(Rencarex®) in five completed studies during the development program for Rencarex®. The trials 
were conducted with both the murine (mG250) and the chimeric version of the antibody 
(girentuximab), both of which are virtually indistinguishable in their ability to target RCC tumors 
and in their binding capacity to the CAIX antigen. One open label single dose phase 1 study (WX- 
2007-10-HV) in healthy volunteers (girentuximab monotherapy), two phase 1/2 studies in 
combination therapy with low dose Interleukin-2 (WX-2000-04-gil) and Interferon-α (WX-2001-05- 
IFN), both in patients with metastatic RCC, one phase 2 girentuximab monotherapy study (WX- 
2000-01-nak) in advanced RCC patients, and one adjuvant placebo-controlled double-blind phase 
3 study in patients with clear cell RCC and high risk of recurrence (WX-2003-07-HR) were 
conducted. In addition, unlabelled girentuximab was administered in two further studies LUD 2002-
003 and LUD 98-011, where patients received also radiolabelled girentuximab.  
In a single-dose phase 1 study (Steffens et al., 1997), the injection of trace-labelled antibody was 
well tolerated and no side effects were seen.   
In an open label Phase 1 study (WX-2007-10-HV) 12 healthy volunteers received a single IV dose of 
20 mg of unlabelled girentuximab. Safety and tolerability of girentuximab in healthy volunteers as 
assessed by AEs, vital signs, 12-lead ECG, clinical laboratory evaluations, physical examination 
findings, and HACA. No safety concerns were raised.  
In a multiple dose phase 1 study (LUD 98-011) repeated doses of up to 50 mg/m2 of girentuximab 
were administered for more than 6 weeks in patients with metastatic RCC without significant 
toxicity.  
In a phase 2 study with a 12-weeks plus 8 weeks extension treatment regimen (WX-200001- NAK), 
the weekly IV administration of 50 mg girentuximab was safe and well tolerated by all patients 
without significant immunogenic effects or direct side effects. Intravenously administered 
girentuximab appears to be immune-silent and opens the possibility for repeated treatment.  

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The treatment with girentuximab in combination with IL-2 (WX-2000-04-GIL) or IFNα-2a (WX- 2001- 
05-IFN) appears to be safe in all investigated doses and schedules. The vast majority of adverse 
events were mild to moderate, transient, fully reversible and reflected mostly the constitutional 
side effects known to occur under treatment with IL-2 or IFNα-2a. Due to the combination of 
girentuximab with these cytokines, causal relationship can only be assessed to the combination 
regimen and not to girentuximab alone.  
A total of 855 patients participated in study WX-2003-07-HR [ARISER trial]. Approximately half of 
these received girentuximab. HACA formation was followed and patients‟ HACAs were 
characterized for their neutralising properties and their impact on their girentuximab serum levels. 
8.6% of the patients treated with girentuximab (37 patients out of 431) developed neutralising 
HACAs, whereas, only for 2.4% of the patients, the formation of neutralising HACAs had a relevant 
impact on their girentuximab level during the 24-week long treatment phase. The earliest time 
point when a girentuximab level was persistently no longer measurable was in Week 12 of the 
treatment period.  
The AEs reported during study WX-2003-07-HR were predominantly as expected for this patient 
population. Overall, the frequency of patients reporting any AE, any SAE or any grade 3/4/5 AE, 
regardless of relationship, was comparable across both treatment arms. No treatment related 
deaths occurred during the study, and no patients were discontinued due to drug related SAEs. One 
girentuximab-treated patient who discontinued due to related cytokine release syndrome 
recovered completely. Overall, treatment with girentuximab was seen to be safe.  
Table 6 lists the safety results for the four clinical studies in patients conducted with unlabelled 
girentuximab in the development program for Rencarex®.  
 
Table 6: Clinical Studies in Patients with Unlabelled girentuximab – Dose Regimen, Incidence of 
HACA Formation and Safety Profile 
Trial code  
WX-2000-01-NAK  
(Monotherapy)  
 
WX-2000-04-GIL  
(Combination therapy 
with IL-2)  
 
WX-2001-05-IFN  
(Combination 
therapy with IFN- α) 
WX-2003-07-HR  
(Monotherapy)  
Design  
An open label single 
arm Phase 2 study of 
girentuximab 
administered weekly 
by IV infusion to 
advanced renal cell 
carcinoma patients  
A Phase 1/2 study 
with girentuximab 
and low dose IL-2 
plus periodic IL-2 
pulsing in advanced 
and metastatic renal 
cell carcinoma 
patients  
A Phase 1/2 study 
with girentuximab 
and IFNα-2a in 
metastatic renal cell 
carcinoma patients  
A randomized, double 
blind, Phase 3 study to 
evaluate adjuvant 
girentuximab treatment 
versus placebo in 
patients with clear cell 
RCC and high risk of 
recurrence  
Clinical Phase  
2  
 
1/2  
 
 
1/2  
3  
Patient Exposure 
(total of 545 
patients, incl. 
patients from 
LUD 98-011)  
36  
36 Caucasian 
12 female, 24 male  
35 
34 Caucasian  
1 Asian 
8 female, 27 male  
31  
31 Caucasian 
8 female, 23 male  
431 
403 Caucasian  
10 Asian 
10 African 

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8 Hispanic 
156 female, 275 male  
Girentuximab 
dose regimen  
50 mg once weekly for 
12 weeks  
 
20 mg once weekly 
for 11 weeks  
 
20 mg once weekly 
for 11 weeks  
Single loading dose of 
50 mg (Week 1) 
followed by weekly 
infusions of 20 mg of 
girentuximab or placebo 
over 24 weeks  
Incidence of 
HACA formation* 
(%)  
2 out of 36 (5.6%) no 
clinical symptoms  
2 out of 35 (5.7%) no 
clinical symptoms  
 
None out of 31 (0%) 
 
51 patients out of 431* 
(11.8%) 
37 patients out of 431**  
(8.6%) with neutralising 
HACAs  
Safety profile  
• 13 SAEs, not 
treatment-related 
• 147 Non-Serious 
AEs (12.2% related)  
• 4 SAEs, not 
treatment-related • 
420 Non-Serious AEs 
(81.9 % related) 
• Most AEs typical  
for IL-2 (e.g. fever, 
chills)  
• 6 SAEs, not 
treatment-related • 
183 Non-Serious 
AEs (39% definitely 
related) • Most AEs 
typical for IFN (e.g. 
fever,  
chills, flulike 
symptoms)  
• 72 SAEs, only 1 
treatment-related 
(placebo)  
• 66.5% of patients 
experienced AEs 
• 21.6% were 
considered treatment-
related (21.0%  
placebo, 22.3% 
girentuximab)  
 
*Any HACA regardless of neutralising or non-neutralising properties ** Number of patients in the active treatment arm  
Minimal HACA responses were observed and were not associated with clinical symptoms. No 
allergic reactions have been observed so far.  
No causal relationship between deaths occurred during or after study termination and 
girentuximab was observed.  
In conclusion, from the data collected in clinical studies, it appears that the chimeric antibody 
girentuximab is well tolerated, and safe. In addition, girentuximab has a low immunogenicity as the 
production of HACAs against the girentuximab antibody was only seen very rarely. 
 
1.2.3.2.2 
Overview on Safety of 89Zr-TLX250 (89Zr-TLX250)  
 
The risks associated with the injection of Zirconium-89 are considered low. The mean effective dose 
after administration of a Zirconium-labelled monoclonal antibody is 0.6 mSv/MBq (18). Radiation 
exposure of 37 MBq 89Zr‐labelled girentuximab will be approximately 22 mSv. Considering the 
patient category (majority older than 50 years and/or metastatic disease) the relative dose will be 
22/5 = 4.4 mSv and this is an acceptable dose according to the ICRP 62 (ICRP, 1992).  
In a single-centre, single-arm and open label proof-of-concept study (No. 08121986, ZIRDEE), 
conducted and recently completed by Radboud, 30 patients suspected of primary, recurrent or 
metastatic ccRCC and in whom conventional diagnostics were inconclusive, were included. A 89Zr-
TLX250 PET/CT was acquired 4-5 days after single intravenous injection of 5 mg 89Zr- TLX250 (37 
MBq) (19).  

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No dosing related AEs were reported for the 30 included patients. Three patients experienced mild 
diarrhoea of whom 2 patients had pre-existing bowel complaints such as stoma and colitis.  
A bridging dosimetry study (ZIRDOSE), looking at both a 5 mg and a 10 mg mass dose of 
girentuximab, investigating the safety and diagnostic performance of 89Zr-TLX250 PET/CT in 10 
patients with suspected ccRCC, based on incidental imaging evidence of a renal mass, is completed 
and in the analysing and reporting phase. Preliminary safety data did not prompt any safety concern 
over the treatment. In the course of the study, no treatment-related SAEs or SUSARs were reported 
from any of the 10 patients. The severe SAE of post operational bleeding was considered by the 
investigator as not related to the study treatment. A total of 7 AEs were experienced by 4 patients. 
An unlikely 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. 
Nausea is an expected side effect of girentuximab.  
To date, the on-going ZIRCON phase 3 trial has dosed 29 patients with 89Zr-TLX250 where no 
treatment -related SAEs have been reported. The non-treatment related SAEs consisted of grade 3 
anaemia, pleural effusion, increased C-reactive protein and a grade 5 arterial perforation through 
a surgical complication. Nine grade 1 AEs have been reported where only one incidence of diarrhea 
and abdominal pain were assessed as possibly related to the study drug. Two grade 2 events of 
abdominal pain and constipation were reported but were not considered to be related to 89Zr- 
TLX250.  
 
1.2.3.2.3 
Girentuximab, 
Radiolabelled 
with 
Other 
Diagnostic 
Radionuclides  
 
Altogether, during more than 2500 chimeric girentuximab administrations allergic-type reaction 
were not observed. In the radioimmunotherapy (RIT) trials, no side effects that could be attributed 
to the girentuximab itself were observed (7,12,13).  
In radioimmunotherapy trials (RIT) with multiple administrations of radiolabelled girentuximab, 
Telix International Pty Ltd 40, HACA responses were observed in approximately 15% of patients 
(Stillebroer et al., 2013). Although HACA formation did not result in any clinical signs or symptoms 
or biochemical abnormalities, it prevented further treatment with radiolabelled girentuximab due 
to immune complex formation of the radiolabelled antibody in circulation and subsequent fast 
blood clearance of the immune complexes, causing reduced accumulation of radiolabelled 
girentuximab in the tumor (11).  
In summary, there are a total of 265 unique patients from the three Wilex sponsored studies: 
WX/20- 001, LUD 2002-003, and LUD 98-011. It might be noteworthy that study LUD 98-011 
administered girentuximab (four infusions) and 131I-girentuximab (two infusions).  
The most comprehensive available safety data for radiolabelled girentuximab exist from patients 
which were undergoing diagnostic PET imaging with 124I-girentuximab, which was evaluated in a 
diagnostic Phase 3 study in 196 patients with suspected ccRCC (Protocol WX/20-001, an open- label, 
comparative study of positron emission tomography/computed tomography (PET/CT) versus 
diagnostic CT for the detection of ccRCC in pre-surgical patients with renal masses). Safety data 
from this study and two additional studies involving use of 124I- or 131I-girentuximab are presented.  

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All patients in the safety population received at least one dose of study treatment (i.e., 124I- 
girentuximab, girentuximab, or 131I-labelled girentuximab) (20).  
In Study LUD 2002-003, one of the 25 patients tested developed HACA in response to the infusion. 
All physical examination results for this patient were normal.  
Transient slight changes in blood pressure and pulse were recorded on day 1 for some patients 
during the infusion, but the vital signs of most patients were not affected. None of the systolic 
blood pressure readings met the criteria for decreasing the rate of or discontinuing the infusion.  
In Study LUD 98-011, 13 patients were observed for at least 28 days after the first dose to assess 
toxicity. All patients were HACA negative after treatment except for one patient who developed 
HACA after the second weekly infusion.  
In Study WX/20-001, 204 patients received a single 13.7 mg infusion of 124I-girentuximab, and 198 
of these patients had at least one baseline and one follow-up (post-treatment) blood sample 
evaluable for HACA evaluation. Samples for HACA assessment were obtained at all of the study- 
defined time points for 169 of these patients. 142 out of 198 patients (71.7%) were negative for 
HACA at all time points, while 56 out of 198 patients (28.3%) were positive for HACA at one or more 
time points. Specifically, not all patients tested positive for HACA had a clinically relevant HACA 
conversion to positive for neutralising capability.  
In reviewing positive HACA responses of the 56 positive HACA patients, 41 patients (20.7%; 41/198) 
had only one positive HACA sample and, of these forty-one patients, 10 were HACA positive within 
48 hours before surgery. 30 patients had a positive HACA result at the last follow- up visit 8 to 9 
weeks after surgery, and 1 subject 4 to 5 weeks after surgery. Only 15 patients (7.6%; 15/198) had 
more than 1 positive HACA sample. 
In total, 44 of the 56 HACA converted patients had a positive sample at 8 to 9 weeks after surgery; 
while 11 patients (20%) who developed HACA antibodies reverted to HACA negative within 
approximately two months (study duration). For one patient the last follow up sample to be taken 
on Weeks 8-9 is missing. This observation of reconversion back to HACA negative is an expected 
immunologic response. The waning of HACA positivity could explain the absence of any clinically 
important findings in those patients who did convert to HACA positive versus those who remained 
HACA negative. Importantly, the patients remaining HACA positive [+] did not have any safety 
findings that differentiated them from HACA negative [-] patients implying HACA levels in these 
remaining HACA[+] patients were also decreasing.  
The incidence of AEs considered to be related to 124I-girentuximab (12.5%) and of AEs that were 
severe or worse in intensity by CTCAE grading (21.4%) for these 56 HACA-positive patients was 
similar to that of all patients (13.3% and 16.4%, respectively). The incidence of SAEs was also similar 
(16.1% for patients with positive HACA results versus 14.6% for patients overall).  
 
1.2.3.2.4 
Girentuximab and mG250, Radiolabelled with Therapeutic 
Radionuclides for RIT  
 
Multiple studies have been conducted with 131I-labelled girentuximab in order to investigate the 
potential to use these antibodies for radioimmunotherapy (RIT). Due to the lack of efficacy, this 
development was discontinued.  

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1.2.3.2.5 
Overview on Safety  
 
 Common Adverse Events  
 
Common AEs are defined as those occurring in more than 2% of patients in Study WX/20-001. The 
threshold of 2% was used due to the low incidence of AEs, the typical higher threshold e.g. 5%, 
would result in fewer listed ʺcommonʺ AEs. Low AE rates are expected in diagnostic 
radiopharmaceutical imaging agents and setting the threshold at the lower 2% allows the listing of 
the few AEs that were observed.  
Safety information for Studies LUD 98-011 (administration of girentuximab with trace 131I-labelled 
girentuximab to patients with RCC) and WX2007-10-HV (administration of girentuximab to healthy 
volunteers) are presented as supportive data and can be found in the above sections.  
To date, 230 patients have been treated with 124I-girentuximab in clinical trials. The following AEs, 
for which a causal relationship to the study medication could not be excluded, have been reported 
in at least 5% of patients. These adverse drug reactions (ADRs) are presented in descending order 
of frequency and are considered expected for 124I-girentuximab: headache, nausea, diarrhoea, 
dizziness, dysgeusia, pollakiuria, flushing and temporary increase in liver function tests (ALT, AST).  
Single cases of mild administration site reactions (e.g. redness, pain, itching) and mild allergic 
reactions (e.g., rash, chills, feeling hot) have been reported and are also considered expected.  
Table 7 presents the most commonly reported AEs in the two main studies for 124I-girentuximab 
(Studies WX/20-001 and LUD 2002-003). Adverse events are presented by decreasing SOC 
incidence in Study WX/20-001. AEs reported by at least one subject in Study LUD 2002-003 but 
reported by less than 2% of patients in Study WX/20-001 are presented for comparison.  
 
Table 7: Summary of Adverse Events Reported Following a Single Dose of 124I-girentuximab Reported 
in at Least 2% of Patients for Study WX/20-001 and at Least One Subject for Study LUD 2002-003 – 
Safety Population 

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Table 7: Summary of Adverse Events Reported Following a Single Dose of 124I-girentuximab Reported 
in at Least 2% of Patients for Study WX/20-001 and at Least One Subject for Study LUD 2002-003 – 
Safety Population (...continued) 
 
 
 

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 Deaths   
 
No deaths were reported during Studies LUD 2002-003 and WX-2007-10-HV. A total of 5 patients 
had fatal SAEs in the respective other studies. All were considered unrelated.  
Four (1.8 %) patients died during Study WX/20-001: disease progression, extravasation of urine, 
pulmonary embolism, and sepsis (one subject each). Although all four patients had AEs with an 
outcome of death, three of these patients had death as the reason for study discontinuation. The 
fourth subject (Subject WX/20-001/013006) discontinued from the study because of an SAE 
(disease progression), which began 5 days after infusion. The subject died 30 days later as a result 
of that SAE that was recorded as the reason for study discontinuation. None of the deaths were 
considered to be related to 124I-girentuximab.  
One subject (Subject LUD 98-011/g250-20) in Study LUD 98-011 experienced a fatal SAE (acute 
renal failure, CTCAE Grade 4) that was considered unrelated to study treatment. 
 
1.3 
Rationale for conducting this study  
 
89Zr-Girentuximab is under clinical development as a PET/CT imaging radiopharmaceutical 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. 
 
CAIX has recently emerged as a very attractive therapeutic target due to the following features:  
 
 CAIX is expressed in several cancers. Especially, it is expressed in 70% to 90% of bladder 
cancers but not in normal urothelial tissue (8). 
 CAIX is expressed on the membrane of Non-Muscle-Invasive Bladder Cancer cells (8,21).  
 
Klatte et al. showed that CAIX has a role as a diagnostic, prognostic, and therapeutic molecular 
marker. Because CAIX expression and is highly expressed in noninvasive, low-grade bladder cancer, 
the evaluation of CAIX may be a useful adjunct to diagnostic cytology, and intravesical CAIX targeted 
therapy may be effective in these high CAIX-expressing tumors. Likewise, because metastatic 
tumors express high CAIX, an evaluation of systemic CAIX-targeted therapy as a therapeutic 
approach is warranted (8). 
 
The current project will consist of an intravesical instillation of anti-CAIX antibody (girentuximab) 
labeled with an activity of 37 MBq of positron-emitting zirconium-89.  
In previous clinical studies, intravenous administration of Zirconium-89 (89Zr) labeled monoclonal 
antibodies was proven to be safe.  
Furthermore, it has been clearly shown that, after an intravesical instillation, a radiolabeled 
antibody remains confined in the bladder without extravasation in the general circulation (6,7). 
Thus radiation is limited to the bladder wall. In the clinical pilot study performed with an antibody 

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labeled with an activity of up to 740 MBq of an alpha-emitting radionuclide (bismuth-213) much 
more irradiating than zirconium-89 no toxicity at all has been observed. Thus no toxicity is expected 
in the current proposal consisting in an instillation of 37 MBq of zirconium-89 followed two hours 
later by a lavage of the bladder. 
One of the objectives of this study is to assess the biodistribution of 89Zr-girentuximab in whole 
body if it exists.  
After establishing the targeting properties of 89Zr-Girentuximab PET/CT imaging tracer in NMIBC, it 
should be interesting to develop a new targeted therapy using girentuximab- radiolabelled with a 
therapeutic radionuclide such as Astatine-211 (211At-Girentuximab).  
An alpha-immunotherapy project of non-muscle-invasive bladder cancer was initiated by Atonco 
with an alpha-emitting radionuclide labeled with astatine-211. 
 
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 
 
The extensive clinical experience with radiolabeled girentuximab has provided strong clinical 
evidence to support its use as a targeted PET imaging agent in clear-cell renal cell cancer. 
CAIX, is a cell surface antigen expressed in 70% to 90% of bladder cancer NMIBC but not in normal 
urothelial tissue; therefore, it represents an optimal therapeutic target. There may be a role for 
CAIX as an intravesical target for instillation therapy(8).  
Once 89Zr-Girentuximab has been shown to be safe, we will develop a treatment of bladder cancer 
NMIBC for therapeutic purposes with girentuximab radiolabeled with a therapeutic radionuclide 
such as: 211Astatine. 
Especially as local treatments such as mitomycin C and BCG therapy are in short supply worldwide, 
it is important to offer alternative treatments to postpone cystectomy. 
 
1.4.3 
Overall risks 
 
In previous clinical studies, intravenous administration of Zirconium-89 (89Zr) labeled monoclonal 
antibodies was proven to be safe (18,22). 
Although never observed in previous trials, allergic-type reactions are possible during and 
immediately following the intravenous administration of girentuximab. In a total of more than 2000 

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intravenous administrations of radiolabelled murine and chimeric girentuximab to humans, no 
allergic-type reaction was observed.  
Moreover, it has been clearly shown that, after an intravesical instillation, a radiolabelled antibody 
remains confined in the bladder without extravasation in the general circulation (6,7) making an 
allergic reaction unlikely. No toxicities have been reported in these two studies. 
In PERTINENCE study, even if no toxicity related to intravesical 89Zr-Girentuximab administration 
is expected, patients will be carefully monitored after intravesical 
89Zr-Girentuximab 
administration. 
Some adverse events related to intravesical administration are expected: mictional burning, 
deposition or scaling in the urine, pollakiuria, fatigue, fever and haematuria. Patient will be 
informed to contact the investigator if one of these adverse events occurs. 
 
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 (15). 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. 
 
The current PERTINENCE clinical trial will consist in intracavitary (intravesical) instillation of the 
same radiopharmaceutical ʺ89Zr-girentuximabʺ used in the Telix phase 3 ZIRCON clinical trial with 
systemic intravenous injection and using the same activity (37 MBq).   
 
With regard to the potential toxicity following this administration route, we refer to two previous 
preclinical and clinical studies performed with a different antibody, namely anti-Epidermal Growth 
Factor Receptor (EGFR) labeled with bismuth-213, an alpha-emitting radionuclide.  
 
In a preclinical study with an orthotopic human bladder carcinoma mouse model, an activity of up 
to 0,925 MBq was intravesically instilled (7). Excellent retention of the therapeutic 
radiopharmaceutical in the bladder with negligible systemic activity was observed.  
 
It is important to note that no macroscopic urothelial lesions caused by a-particle irradiation was 
observed.  
In a subsequent clinical pilot study, an activity of up to 821 MBq (22mCi) of the same 
radiopharmaceutical was intravesically instilled in 12 patients (6). 
 
It was clearly shown that 
213Bi activity remained in the bladder with no systemic uptake and reflux 
into the ureters as observed in the preclinical study (Figure 9). 

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Figure 9: Distribution of 
213Bi-anti- EGFR MAb after intravesical instillation visualized via SPECT/ CT 
imaging: all activity remains in the urinary bladder.  
 
All 12 patients treated with the 
213Bi-immunoconjugate showed excellent tolerance without any 
signs of adverse effects. 
213Bi was not detected in blood samples taken from patients during 1 to 2 
hours after treatment.  
 
Overall, no toxicity at all was observed in both preclinical and clinical studies.  
The antibody used in the PERTINENCE study is different but the same retention inside the bladder 
should be expected due to the size of the antibody molecule.  
The radionuclide also is different but a higher toxicity could be expected with alpha-emitting 
bismuth-213 radionuclide than with positron-emitting zirconium-89 due to a much higher Linear 
Energy Transfer (LET).  
Consequently, no toxicity at all is expected in the PERTINENCE study after intravesical instillation 
of 37 MBq of 89Zr-girentuximab.  
 
According to the information described above, it appears that the benefit/risk ratio will be clearly 
in favour of the benefit to the patient. 
 
The results of Pertinence study may contribute to the development of a new targeted therapy for 
Non-Muscle-Invasive Bladder Cancer (NMIBC) with girentuximab labelled with a therapeutic 
radionuclide such as astatine-211 (211At-Girentuximab).  
 

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2. 
OBJECTIVES 
 
2.1 
Primary objective(s) and endpoint 
 
2.1.1 
Primary objective 
 
The primary objective of this study is to assess the biodistribution of 89Zr-girentuximab.  
 
2.1.2 
Endpoints of primary objective 
 Bladder uptake will be evaluated quantitatively using SUVmax, SUVmean and (Bq/ml) at 
different time points (T0, T0+2h, T0+20h and T0+44h)  
 The activity retained by the bladder at T0 will be assessed by the difference between the 
instilled activity (Bq) and the activity after rinsing measured in the saline solution used for 
rinsing (Bq). 
 Biodistribution in whole body will be assessed visually and quantitatively by PET/CT imaging 
of whole body at T0+2H and quantitatively by assessing the 89Zr-Girentuximab activity in 
blood at T0+20h. Another PET/CT imaging of whole body will be performed at T0+44h in 
case of positive blood radioactivity at T0+20h. 
 
2.2 
Secondary objective(s) and endpoint 
 
2.2.1 
Secondary objectives 
 
1. Assess the safety and tolerability of 89Zr-girentuximab administered by intravesical 
instillation. 
2. Radiation protection management 
3. Assess the degree of CAIX expression by immunohistochemistry of the tumor sample. 
 
2.2.2 
Endpoints of secondary objectives 
 
1. The occurrence and the frequency of adverse events up to Day 30 after 89Zr-
girentuximab administration. 
2. Radiation protection management:  
 
 Radiation exposure of staff (extremities, lens and Whole body: µSv). 
 Radiopharmaceutical management from intravesical instillation to elimination 
(surfasic contamination: counts/cm2 or Bq/cm2). 

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3. The expression of CAIX will be assessed in TURBT or cystectomy tumor sample by 
immunohistochemistry (IHC). 
 
 
 

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3. 
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.  
 
3.1 
Population description 
 
Patients with Non-Muscle-Invasive Bladder Cancer (NMIBC) requiring a radical cystectomy will be 
included in this study just before their surgery. Cancer treatment will not be delayed by study 
participation. 
 
3.2 
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. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, 
and other study procedures. 
3. Female or male, Age ≥ 18 years at time of study entry. 
4. PS: 0 or 1.  
5. Clinical evidence of NMIBC based on cystoscopy and proven histologically of papillary 
tumors. 
6. Histologically-confirmed pTa Grade 3 or pT1 Grade 3 bladder cancer patients relapsing 
without muscle invasion. 
7. Negative sterile Urine cytobacteriological testing at baseline (T0). 
8. Consent to use a contraception method for at least 42 days after administration of 89Zr-
girentuximab. 
9. Patient has valid health insurance. 
10. Negative serum pregnancy test in female patients of childbearing potential at screening.  
 
3.3 
Non-inclusion criteria 
Patients should not enter the study if any of the following non-inclusion criteria are fulfilled: 
 
1. Patient with urinary incontinence. 
2. Known hypersensitivity to girentuximab. 
3. Exposure to any experimental diagnostic or therapeutic drug within 30 days prior the date 
of planned administration of 89Zr-girentuximab 

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4. Exposure to any radiopharmaceutical within 30 days prior to the administration of 89Zr-
girentuximab 
5. Patients suffering from a bladder cancer at stage pT2, pT3 or pT4 
6. Serious non-malignant disease that may interfere with the objectives of the study or with 
the safety or compliance of the patient; as judged by the investigator 
7. Concomitant cancer in the past 5 years except cutaneous cancers (except melanoma) and 
in situ carcinoma 
8. Prior chemotherapy, radiotherapy (other than short cycle of palliative radiotherapy),  
immunotherapy within 21 days of 89Zr-girentuximab administration 
9. TransUrethral Resection of Bladder Tumor (TURBT), BCG or Mitomycin C endovesical 
instillations within 10 days before 89Zr-girentuximab 
10. Patients with known HIV, HBV and HCV infections, 
11. Pregnant or likely to be pregnant or nursing patient. 
12. Mental impairment that may compromise the ability to give informed consent and comply 
with the requirements of the study 
13. Persons deprived of their liberty, under a measure of safeguard of justice, under 
guardianship or placed under the authority of a guardian. 
 
As patients are enrolled 10 days before the IMP administration, a confirmation of negative 
pregnancy test result from urine should be performed within 72 hours prior 89Zr-girentuximab 
administration. 
Validated methods of contraception for both men and women are pill, condom, intra-uterine 
device.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.  
 
3.4 
Withdrawal of patients from study  
 
3.4.1 
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. 

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3.4.2 
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.  
 
3.5 
Patients replacement  
 
A patient who is included into the study, but then fulfils any one of the following, will be considered 
as drop-out: 
 
Has not received 89Zr-TLX250 administration; 
 
Did not undergo 89Zr-TLX250 PET/CT imaging after intra-vesical 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 intra-vesical 89Zr-TLX250 will need to get all the examinations and blood draws as for the 
final study visit. 
 
 

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4. 
STUDY PROCEDURE 89Zr-TLX250 PET/CT SCAN 
 
4.1 
Study drug 89Zr-TLX250 
 
4.1.1 
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.  
The chemical formula, without the 89Zr, is C6460H1006N1718O2018S48 with a molecular mass of 146.5 
kg/mol. 
 
4.1.2 
Pharmaceutical Properties 
 
89Zr-TLX250 is formulated as a solution for intravesical instillation in glass vials at the nominal 
dosage strength 37 MBq (±10%) for intravesical instillation use. The 89Zr-TLX250 drug product is 
manufactured as “ready-to-use”. The composition of 89Zr-TLX250 solution for intravesical 
instillation includes the active pharmaceutical ingredient in a buffered solution without other 
excipients.  
A complete record of batch numbers and expiry dates of all study medication will be maintained in 
the trial master file (TMF). 
 
4.1.3 
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.  
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. 
 
4.1.4 
Packaging and Labelling 
 
89Zr-TLX250 solution for intravesical instillation 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  

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 
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. 
 
4.1.5 
Drug Logistics and Accountability  
 
4.1.5.1 
Supply, Storage, Dispensation and Return  
 
89Zr-TLX250 solution for intravesical instillation 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) 
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 manufacturer who shall arrange 
appropriate supply of IMP. Upon establishment of patient eligibility (see Section 3), the clinical site 
manager will order individualized doses of 89Zr-TLX250 solution for intravesical instillation, via the 
manufacturer 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 inform 
manufacturer. 89Zr-TLX250 for intravesical instillation 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 intravesical instillation 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 intravesical instillation will be kept in a secure, 
temperature-controlled, restricted-access location and in accordance with applicable regulatory 

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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.  
 
4.1.5.2 
Drug Accountability  
 
The radiopharmacist will confirm receipt of the study drug by e-mail 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. 
 
4.2 
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. 
 
4.2.1 
Dosage and Administration 
 
This is sufficient to draw up the patient dose of 37 MBq of 89Zr- TLX250, adjusted to 10 mg of 
girentuximab at the time of injection.  
The study medication will be prepared as individual syringe in ICO radiopharmacy by a dedicated 
pharmacist within one hour of administration.  
The investigator should check that the urine cytobacteriological testing is negative before 
intravesical instillation to ensure the absence of germs. 
The 89Zr-Girentuximab solution (about 10 ml) will be administered into the emptied bladder 
through a urethral catheter using natural urinary tract (see intravesical instillation procedure in 
appendix 7). 
The syringe will be washed with 30 ml of saline solution which will be also injected into the bladder. 
The urethral catheter should be removed. 

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Patients will be asked to turn over repeatedly to ensure equal distribution of 89Zr-Girentuximab in 
the bladder. 
The 89Zr-Girentuximab should be maintained in the bladder for no more than 1.5 hours: duration 
of 89Zr-Girentuximab administration. 
Then, the patient will be asked to drink water and urinate to rinse the bladder, the patient will drink 
water again and the first PET/CT imaging centered on the bladder will be performed about 2 hours 
after instillation. 
 
The  urethral catheter and the urine activity will be measured. 
A whole body imaging should be performed 2 hours after 89Zr-Girentuximab administration (4 hours 
after instillation) (see intravesical instillation procedure in appendix 7). 
 
The investigator or his/her designee will administer the study drug to the subjects, exercising 
accepted medical practices. Under no circumstances will the investigator allow study drugs to be 
used otherwise than as directed by this clinical study protocol. Study drug administration will be 
done under direct medical supervision. 
 
4.2.2 
89Zr-TLX250 PET/CT Imaging  
 
Imaging sessions are necessary to check the safety of intravesical application of 89Zr-TLX250 
pharmaceuticals. Two aspects will be studied:  
 
T0: At the end of 89Zr-TLX250 administration: 2 hours after intravesical instillation, , a first 
imaging session centred on the bladder will be performed (with full bladder) and will allow 
to evaluate the possibility to identify the 89Zr girentuximab uptake surface and to measure 
tumor and normal bladder wall surface. Spatial distribution of PET/CT images will cover the 
lone bladder. PET acquisition duration will be adjusted to allow a sufficient count statistics 
for a good quality of activity measurements in main organs. 
 
T0 + 2 hours: a whole body scan will be performed (with empty bladder), from the skull 
base to the mid-thigh, to ensure that no residua 89Zr-TLX250 pharmaceutical occurred 
outside the bladder and spread in the rest of the body. During the whole body scan, the 
specific step including the bladder will be designed. 
 
T0 + 20 hours (day 1): a new imaging session centred on the bladder will be performed 
(same protocol as first session) in order to quantify the remaining activity and calculate the 
decay of the later. The aim is to check that there is no residual radiopharmaceutical outside 
the bladder through the urethra. 
On day 1, a blood sample will be drawn in order to check the absence of activity from 
residual 89Zr-TLX250 in blood.  
 
T0 + 44 hours (day 2):  
 If blood radioactivity testing on day 1 is negative, a bladder scan should be 
performed on day 2 (T0 + 44 hours). 
 If blood radioactivity testing on day 1 is positive, a Whole body scan should be 
performed on day 2 (T0 + 44 hours). This scan will permit to localise the uptake of 
the residual pharmaceutical. 

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In total, 4 imaging sessions will be performed, including a whole body scan and in case of residual 
activity in the day 1 blood sample, a second whole body scan will replace the bladder centred scan. 
 
PET studies will be performed with a PET/CT hybrid system. A CT acquisition will be coupled to a 
PET acquisition for attenuation correction and anatomical tracking. 
Low-dose CT acquisition parameters will be those usually used namely: 
 
Field: several fields of view allowing visualization of the bladder and whole body. 
 
Number: four acquisition times: 
 
Time 0: 2 hours after instillation: 
 Full bladder imaging: one step centred on the bladder after CT acquisition of the step. 
 Time 1: 4 hours after instillation:  
 Whole body scan after scout view and low dose CT acquisition, to cover area from 
skull base to mid-thigh. The step on the bladder is included into this whole body scan. 
 Time 3: 20 hours after instillation (day 1): 
 One step acquisition centred on bladder with low dose CT 
 Time 4: 44 hours after instillation (day2): depending on the day 1 blood sample results (in 
terms of activity in Bq/ml), 
 In case of negative result (no activity i.e. background): One step acquisition centred 
on bladder with low dose CT. 
 In case of positive result (activity > 2.5 times background): Whole body scan after 
scout view and low dose CT acquisition, to cover area from skull base to mid-thigh. 
The step on the bladder is included into this whole body scan. 
 
Comment: These times should be adapted according to practical arrangement of intravesical 
instillation. 
 
Standard whole body scan = 100 kV, 5 mm, Acq 16x1,2 mm, pitch 1, CAREDOSE4D, CAREkV 
 
One step high accuracy CT: 120 kV, 4mm slices every 4 mm and 0.85 pitch CAREDOSE4D, 
CAREkVOne step low dose CT: 100 kV, 5mm, Acq 16×1.2mm, pitch, CAREDOSE4D, CAREkV 
 
The CT acquisitions centred on the bladder will visualize a field of about 20 cm and consequently 
will deliver a low dose corresponding to a DLP of around 130mGy.cm and an effective dose of 
around 3 mGy. 
The whole body CT acquisitions, from skull base to mid-thigh, will visualize a field depending of the 
height of the patient. For standard 170cm height, this will deliver a low dose corresponding to a 
DLP of around 350mGy.cm and an effective dose of around 5 mGy. 
The total effective dose resulting from successive CT acquisitions for attenuation correction can be 
estimated from 14 to 16 mSv. This dose should be compared to a diagnostic CT acquisition dose to 
thorax and abdomen, which is about 15 to 16 mSv. 

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4.2.3 
Imaging Analysis 
 
4.2.3.1 
Qualitative 89Zr-TLX250 Tumor Targeting 
 
89Zr-TLX250 tumor uptake will qualitatively be assessed, considering whether or not 89Zr-TLX250 
binding the target bladder lesion. 
We would like to show that 
89Zr activity remain in the bladder and that no systemic uptake and 
reflux into the ureters is observed as described in a previous clinical pilot study with intravesical 
instillation of 
213Bi- anti- EGFR MAb (6). 
 
 
4.2.3.2 
Semiquantitative 89Zr-TLX250 Tumor Targeting 
 
SUVs will be calculated for the tumor bladder lesion, considering the measured tumor-bound 
activity, the injected activity dose, and the body weight and height of each patient.  
 
4.2.3.3 
Quantitative 89Zirconium activity in blood 
 
The 89Zirconium activity in the patient blood sample will be determined on day 1 by counting the 
89Zr-TLX250 activity in blood in a calibrated gamma counter. Counting will be performed 
immediately after the end of blood collection in the local nuclear medicine department in order to 
check the absence of activity from residual 89Zr-TLX250 in blood. 
 
4.2.3.4 
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 TURBT or cystectomy 
tumor sample by immunohistochemistry. 
The degree of CAIX expression will be investigated and classified. 
 
4.3 
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.  

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Then, the authorized site representative for the study can order the study drug through the “89Zr-
TLX250 Order Form”.  
4.4 
Blinding  
Not applicable, this is an open-label study.  
 
4.5 
Treatment Compliance  
 
89Zr-TLX250 will be administered by trained study personnel at the site. Details of each 
administration will be recorded in the patient file and in the eCRF. 
  
4.6 
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 3 hours p.a., unless the 
investigator decides otherwise. 
Excretion will occur during the rinsing stage after instillation. No excess excretion is expected after 
rinsing. If happens, only a low fractionation of leakage could occur days after. This is what will be 
studied with quantified imaging of the bladder. The leakage, if any, will be at very low level, lower 
than excretion of standard diagnosis examination after patient release. 
 
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 for one week:  
 
Patients should be advised to observe rigorous hygiene in order to avoid risk of 
contamination of others using the same toilet facility.  
 
One shower per day. 
 
Change of underwear every day. 
 
A double toilet flush is recommended.  
 
Patients should wash their hands thoroughly every time after using the toilet.  
 
After hospital discharge, no distancing from and contact to other persons is required.  
 
The following precautions apply for health care workers:  

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Healthcare personnel are advised to 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). 
A simple calculation with RAD PRO CALCULATOR software, shows that at 100cm from a 37MBq 89Zr 
point source, the dose rate is 4.5 µSv/h.Considering 10 cm of water as shielding due to the body, it 
reduces the dose rate to 3.8 µSv/h. In reality, a fraction of the activity will be remained into the 
bladder so we could expect one tenth or even one hundredth of the activity and so the dose rate 
at 100cm. As comparison, the releasing rule for a patient after iodine-131 treatment impose a 
maximum dose rate of 20 µSv/h at 100cm. 
 
4.7 
Total Radiation Exposure  
 
89Zr-Girentuximab will be administered by intravesical instillation, and should remain inside the 
bladder. The Low Dose CT scan will be performed using a hybrid camera. No dose to organs at risk 
is expected.  
 
If in the worst case, there is a release of the product into the rest of the body, the dosimetry data 
shows a very low impact as it is not of the order of 37MBq (as for intravenous administration) but 
rather of 1 MBq (for intravesical instillation). 
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 intravenous 
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 (23). 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 (24) is used, the resulting effective dose will be 0.551 ± 0.030 mSv/MBq or 20.5 ± 1.1 mSv 
for 37 MBq. 
 
4.8 
Prior and Concomitant therapy 
 
At baseline screening, all prior cancer-related treatments are to be recorded. 
All bladder medications taken within 30 days before 89Zr- Girentuximab PET/CT exam should be 
recorded on the case report form. 
 
 
4.8.1 
Permitted concomitant therapy 
 
TransUrethral Resection of Bladder Tumor (TURBT) in the 30 days after 89Zr- Girentuximab is 
permitted only if the patient's condition requires it. 
 

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4.8.2 
Prohibited concomitant therapy 
 
Chemotherapy, radiotherapy (other than short cycle of palliative radiotherapy), immunotherapy 
are prohibited within 21 days of 89Zr-girentuximab administration. 
These treatments are prohibited within 30 days of 89Zr-girentuximab administration: 
 
Experimental diagnostic or therapeutic drugs. 
 
Any radiopharmaceutical exposure.  
 
5. 
STUDY DESIGN 
 
5.1 
Overview of study design 
 
The research presents the following characteristics: 
- 
Feasibility pilot study  
- 
Imaging trial 
- 
Monocentric  
- 
Non randomized  
- 
Uncontrolled 
- 
Open-label 
- 
Prospective  
 
5.2 
Study design schedule 
 
 
 
Figure 1: Study design schedule 
 
 

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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 administration. 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 
administration. 
 
The following procedures will be performed during the Screening period: 
 
Informed Consent 
 
Subject registration and subject number assignment 
 
Review of eligibility criteria and confirm eligibility 
 
Demographics 
 
Record Medical History  
 
Record Disease History: Histopathological TURBT report 
 
Record NMIB - related treatments 
 
Perform full physical examination with ECOG Performance Status and Vital signs  
 
Review of prior/concomitant bladder medications  
 
Imaging exams: cystoscopy report + bladder diagram 
 
Standard laboratory samples for Haematology and serum Chemistry. 
 
Urine cytobacteriological testing: to be performed, before 89Zr-Girentuximab order: within 10 
days before 89Zr-Girentuximab administration. 
 
Serum β-HCG pregnancy test in women of childbearing potential* and Urine Pregnancy test 
within 72 hours before 89Zr-TLX250 administration. Pregnancy test should not be performed 
for postmenopausal patients**. 
 
* The women under 55 (<55) are considered with childbearing potential. 
** A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause. 
 

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6.1.1 
Medical history  
 
NMIB Disease history will be reported, including date of diagnosis, histological results and previous 
NMIB cancer treatments. 
Relevant findings from medical history (obtained at screening) and physical examination will be 
reported. 
Relevant bladder concomitant medications will be reported. 
 
6.1.2 
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, and temperature), Body weight and height will be evaluated.  
 
6.1.3 
Urine cytobacteriological testing   
 
A urine cytobacteriological testing will be performed before 89Zr-Girentuximab order: within 10 days 
before 89Zr-Girentuximab administration. This testing should be negative before intravesical 
instillation to ensure the absence of germs before instillation.  
 
6.1.4 
Laboratory evaluations 
 
The following laboratory tests will be performed: 
 Haematology: Haemoglobin, haematocrit, platelets, red blood cells, White blood cells and 
differential (neutrophils, basophils, eosinophils, lymphocytes, monocytes). 
 Chemistry: Creatinine, urea, SGOT (AST), SGPT (ALT). 
 Blood or urinary Pregnancy test   
 
 

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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: 
CRGA0067 
- 
Study Sponsor number : 
ICO-2021-03 
- 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 
Tel: +33 (0)2 40 67 98 26 
Project Manager: 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. 
 
 
 

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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: 
 
Patient performance status. 
 
Pre-dose Vital signs. 
 
Blood or urine Pregnancy test (for female patients of childbearing potential) within 72 hours 
before 89Zr-TLX250 administration. 
 
Baseline findings. 
 
Bladder concomitant medications. 
 
Urine dipstick analysis before 89Zr- Girentuximab administration. 
 
The 89Zr-girentuximab solution will be administered through an intravesical instillation using natural 
urinary tract (see section (5.2.1). 
 
Vital signs will be assessed before; 2; 4; 20 and 44 hours after 89Zr-TLX250 administration. 
Adverse event monitoring will be assessed within 2 hours post administration and reported in the 
medical file and the e-CRF. 
 
6.3.2 
89Zr-TLX250 PET/CT Imaging and Dosimetry 
 
Several PET/CT images acquisitions should be performed at the end of 89Zr-girentuximab 
administration on D0, D1 and D2 (see section 4.2.2). 
Urine dipstick analysis at D1 and D2 of 89Zr- Girentuximab administration 
A blood sample (one heparin tube of 4 ml) will be drawn on day 1 to evaluate quantitative 
biodistribution of 89Zr-TLX250 in blood (see section 4.2.3.3). 
 
 
6.4 
Follow-up visit: Day 30 following 89Zr-TLX250 administration 
 
End of study visit will be performed 30 days after 89Zr-TLX250 administration. 
All procedures bellow should be performed:  
 
Evaluation of Performance Status (WHO) 
 
Urine cytobacteriological testing 

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 
Review of AE and SAE + concomitant medications 
6.5 
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: 
- 
Occurrence of significant previously unknown adverse reactions or unexpectedly high 
intensity or incidence of known adverse reactions described such as: any adverse grade > 3 in 
2 patients/3. 
- 
recruitment of patients too low, 
- 
poor quality of the data collected, 
 
 

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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. 
 
 
 
 
 

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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: 
- 
Results in death 
- 
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.  
In PERTINENCE study, we don’t expect any 89Zr-girentuximab adverse event as it will be administered 
intravesically and rinsed out afterwards. It will not diffuse into the general circulation as with 
intravenous administration. 
Clinical experience in 69 patients dosed with a single intravenous 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 in case of 
single intravenous administration. 
Expected adverse events related to intravesical administration are: mictional burning, deposition or 
scaling in the urine, pollakiuria, fatigue, fever and haematuria. Patient will be informed to contact the 
investigator if one of these adverse events occurs. 
 
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 case 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.  

Short Title : 
 
PERTINENCE 
Ref ICO : 
 
ICO-2021-03 
N° EudraCT: 
 
2021-001709-61 
 
2021-001709-61_ Protocole_V2_20220103_PERTINENCE 
68/90 
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.  
 
For this study, all adverse events occurred and medications taken  should be recorded in the e-CRF 
from the date of administration of 89Zr- Girentuximab until 30 days after administration regardless 
of whether they are related to 89Zr- Girentuximab PET/CT. 
 
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, 

Short Title : 
 
PERTINENCE 
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ICO-2021-03 
N° EudraCT: 
 
2021-001709-61 
 
2021-001709-61_ Protocole_V2_20220103_PERTINENCE 
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 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. 
 
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 
sections 7.1.2 and 7.1.5:  
- From informed consent signature up to 89Zr-girentuximab administration: only SAE related to the 
study procedures must be reported to the sponsor. 
- From 89Zr- girentuximab administration up to 30 days post-89Zr- girentuximab 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- girentuximab must be reported without time limit. 
 
Except those that are identified in the protocol as not requiring immediate reporting.  

Short Title : 
 
PERTINENCE 
Ref ICO : 
 
ICO-2021-03 
N° EudraCT: 
 
2021-001709-61 
 
2021-001709-61_ Protocole_V2_20220103_PERTINENCE 
70/90 
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, 
- 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. 
 
 

Short Title : 
 
PERTINENCE 
Ref ICO : 
 
ICO-2021-03 
N° EudraCT: 
 
2021-001709-61 
 
2021-001709-61_ Protocole_V2_20220103_PERTINENCE 
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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. 
 
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. 

Short Title : 
 
PERTINENCE 
Ref ICO : 
 
ICO-2021-03 
N° EudraCT: 
 
2021-001709-61 
 
2021-001709-61_ Protocole_V2_20220103_PERTINENCE 
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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.  
 
In the case of the partner of a patient becomes pregnant, the pregnancy must also be reported to the 
sponsor in the same time frame. However, an authorization must be requested from the patient’s 
partner in order to collect information about the pregnancy. This authorization must be kept in the 
patient’s file. 
 
 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. 
 

Short Title : 
 
PERTINENCE 
Ref ICO : 
 
ICO-2021-03 
N° EudraCT: 
 
2021-001709-61 
 
2021-001709-61_ Protocole_V2_20220103_PERTINENCE 
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8. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION  
 
8.1 
Determination of sample size 
As this study is an exploratory phase, 6 patients will be included in this study.  
The limited sample size has been determined to take into account the fact that this study is a first-in-
man intravesical procedure without intention to treat but necessary to confirm sufficient safety and 
utility for further patients. 
This sample size was also used by Menke-van der Houven van Oordt et al  (25) and should be able to 
reflect some inter-patients variability. 
 
8.2 
Selection of patients to be included in the statistical analysis 
 
All included patients will be analysed. 
 
8.3 
Handling of missing, unused or invalid data 
 
Special care will be taken to minimize any missing data for the 6 patients enrolled. 
 
8.4 
Description of analysis sets 
 
Data will be summarized by frequency and percentage for categorical variables and by median, range, 
IQR, or mean and standard deviation for continuous variables. 
 
 

Short Title : 
 
PERTINENCE 
Ref ICO : 
 
ICO-2021-03 
N° EudraCT: 
 
2021-001709-61 
 
2021-001709-61_ Protocole_V2_20220103_PERTINENCE 
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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. 

Short Title : 
 
PERTINENCE 
Ref ICO : 
 
ICO-2021-03 
N° EudraCT: 
 
2021-001709-61 
 
2021-001709-61_ Protocole_V2_20220103_PERTINENCE 
75/90 
 
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 endpoints:  
 Bladder uptake will be evaluated quantitatively using SUVmax, SUVmean and (Bq/ml) at 
different time points (T0, T0+2h, T0+20h and T0+44h)  
 The activity retained by the bladder at T0 will be assessed by the difference between the 
instilled activity (Bq) and the activity after rinsing measured in the saline solution used for 
rinsing (Bq). 

Short Title : 
 
PERTINENCE 
Ref ICO : 
 
ICO-2021-03 
N° EudraCT: 
 
2021-001709-61 
 
2021-001709-61_ Protocole_V2_20220103_PERTINENCE 
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 Biodistribution in whole body will be assessed visually and quantitatively by PET/CT imaging 
of whole body at T0+2H and quantitatively by assessing the 89Zr-Girentuximab activity in blood 
at T0+20h. Another PET/CT imaging of whole body will be performed at T0+44h in case of 
positive blood radioactivity at T0+20h. 
5) The presence of the major secondary objective endpoints:  
1.  The occurrence and the frequency of adverse events up to Day 30 after 89Zr-girentuximab 
administration. 
2. Radiation protection management:  
 
 Radiation exposure of staff (extremities, lens and Whole body: µSv). 
 Radiopharmaceutical management from intravesical instillation to elimination 
(surfasic contamination: counts/cm2 or Bq/cm2). 
3. The expression of CAIX will be assessed in TURBT or cystectomy tumor sample by 
immunohistochemistry (IHC). 
 
6) Reporting and monitoring of Adverse Events  
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. 
 
 
 

Short Title : 
 
PERTINENCE 
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ICO-2021-03 
N° EudraCT: 
 
2021-001709-61 
 
2021-001709-61_ Protocole_V2_20220103_PERTINENCE 
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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 
IDF III 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. 

Short Title : 
 
PERTINENCE 
Ref ICO : 
 
ICO-2021-03 
N° EudraCT: 
 
2021-001709-61 
 
2021-001709-61_ Protocole_V2_20220103_PERTINENCE 
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The main sponsor responsibilities are: 
 
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. 

Short Title : 
 
PERTINENCE 
Ref ICO : 
 
ICO-2021-03 
N° EudraCT: 
 
2021-001709-61 
 
2021-001709-61_ Protocole_V2_20220103_PERTINENCE 
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 
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). 
 
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. 
 
 

Short Title : 
 
PERTINENCE 
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ICO-2021-03 
N° EudraCT: 
 
2021-001709-61 
 
2021-001709-61_ Protocole_V2_20220103_PERTINENCE 
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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. 

Short Title : 
 
PERTINENCE 
Ref ICO : 
 
ICO-2021-03 
N° EudraCT: 
 
2021-001709-61 
 
2021-001709-61_ Protocole_V2_20220103_PERTINENCE 
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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. 
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. 

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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. 
 
 
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 
(ATONCO) 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 ATONCO 
 
 
Any conflict regarding author’s name appearance will be submitted to the sponsor (ICO) decision. 

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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.  
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 ATONCO. 
 
  
 

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15. 
LIST OF REFERENCES 
 
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muscle-invasive bladder cancer: recommendations from the IBCG. Nat Rev Urol. avr 
2017;14(4):244‑55.  
2.  
Dinney CPN, Greenberg RE, Steinberg GD. Intravesical valrubicin in patients with bladder 
carcinoma in situ and contraindication to or failure after bacillus Calmette-Guérin. Urol Oncol. 
nov 2013;31(8):1635‑42.  
3.  
Brausi M, Oddens J, Sylvester R, Bono A, van de Beek C, van Andel G, et al. Side effects of Bacillus 
Calmette-Guérin (BCG) in the treatment of intermediate- and high-risk Ta, T1 papillary 
carcinoma of the bladder: results of the EORTC genito-urinary cancers group randomised phase 
3 study comparing one-third dose with full dose and 1 year with 3 years of maintenance BCG. 
Eur Urol. janv 2014;65(1):69‑76.  
4.  
Veeratterapillay R, Heer R, Johnson MI, Persad R, Bach C. High-Risk Non-Muscle-Invasive Bladder 
Cancer-Therapy Options During Intravesical BCG Shortage. Curr Urol Rep. sept 2016;17(9):68.  
5.  
Chatal J-F, Kraeber-Bodéré F, Chérel M, Haddad F. Alphatherapy, the new impetus to targeted 
radionuclide therapy? Eur J Nucl Med Mol Imaging. juill 2018;45(8):1362‑3.  
6.  
Autenrieth ME, Seidl C, Bruchertseifer F, Horn T, Kurtz F, Feuerecker B, et al. Treatment of 
carcinoma in situ of the urinary bladder with an alpha-emitter immunoconjugate targeting the 
epidermal growth factor receptor: a pilot study. Eur J Nucl Med Mol Imaging. juill 
2018;45(8):1364‑71.  
7.  
Pfost B, Seidl C, Autenrieth M, Saur D, Bruchertseifer F, Morgenstern A, et al. Intravesical alpha-
radioimmunotherapy with 213Bi-anti-EGFR-mAb defeats human bladder carcinoma in 
xenografted nude mice. J Nucl Med. oct 2009;50(10):1700‑8.  
8.  
Klatte T, Seligson DB, Rao JY, Yu H, de Martino M, Kawaoka K, et al. Carbonic anhydrase IX in 
bladder cancer: a diagnostic, prognostic, and therapeutic molecular marker. Cancer. 1 avr 
2009;115(7):1448‑58.  
9.  
Turner KJ, Crew JP, Wykoff CC, Watson PH, Poulsom R, Pastorek J, et al. The hypoxia-inducible 
genes VEGF and CA9 are differentially regulated in superficial vs invasive bladder cancer. Br J 
Cancer. 22 avr 2002;86(8):1276‑82.  
10.  van de Watering FCJ, Rijpkema M, Perk L, Brinkmann U, Oyen WJG, Boerman OC. Zirconium-89 
labeled antibodies: a new tool for molecular imaging in cancer patients. Biomed Res Int. 
2014;2014:203601.  
11.  Brouwers A, Verel I, Van Eerd J, Visser G, Steffens M, Oosterwijk E, et al. PET 
radioimmunoscintigraphy of renal cell cancer using 89Zr-labeled cG250 monoclonal antibody in 
nude rats. Cancer Biother Radiopharm. avr 2004;19(2):155‑63.  

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12.  van Dijk J, Uemura H, Beniers AJ, Peelen WP, Zegveld ST, Fleuren GJ, et al. Therapeutic effects of 
monoclonal antibody G250, interferons and tumor necrosis factor, in mice with renal-cell 
carcinoma xenografts. Int J Cancer. 15 janv 1994;56(2):262‑8.  
13.  Surfus JE, Hank JA, Oosterwijk E, Welt S, Lindstrom MJ, Albertini MR, et al. Anti-renal-cell 
carcinoma chimeric antibody G250 facilitates antibody-dependent cellular cytotoxicity with in 
vitro and in vivo interleukin-2-activated effectors. J Immunother Emphasis Tumor Immunol. mai 
1996;19(3):184‑91.  
14.  Stillebroer AB, Franssen GM, Mulders PFA, Oyen WJG, van Dongen GAMS, Laverman P, et al. 
ImmunoPET imaging of renal cell carcinoma with (124)I- and (89)Zr-labeled anti-CAIX 
monoclonal antibody cG250 in mice. Cancer Biother Radiopharm. sept 2013;28(7):510‑5.  
15.  Cheal SM, Punzalan B, Doran MG, Evans MJ, Osborne JR, Lewis JS, et al. Pairwise comparison of 
89Zr- and 124I-labeled cG250 based on positron emission tomography imaging and nonlinear 
immunokinetic modeling: in vivo carbonic anhydrase IX receptor binding and internalization in 
mouse xenografts of clear-cell renal cell carcinoma. Eur J Nucl Med Mol Imaging. mai 
2014;41(5):985‑94.  
16.  Abou DS, Ku T, Smith-Jones PM. In vivo biodistribution and accumulation of 89Zr in mice. Nucl 
Med Biol. juill 2011;38(5):675‑81.  
17.  Steffens MG, Boerman OC, Oosterwijk-Wakka JC, Oosterhof GO, Witjes JA, Koenders EB, et al. 
Targeting of renal cell carcinoma with iodine-131-labeled chimeric monoclonal antibody G250. J 
Clin Oncol. avr 1997;15(4):1529‑37.  
18.  Börjesson PKE, Jauw YWS, de Bree R, Roos JC, Castelijns JA, Leemans CR, et al. Radiation 
dosimetry of 89Zr-labeled chimeric monoclonal antibody U36 as used for immuno-PET in head 
and neck cancer patients. J Nucl Med. nov 2009;50(11):1828‑36.  
19.  Hekman MCH, Rijpkema M, Aarntzen EH, Mulder SF, Langenhuijsen JF, Oosterwijk E, et al. 
Positron Emission Tomography/Computed Tomography with 89Zr-girentuximab Can Aid in 
Diagnostic Dilemmas of Clear Cell Renal Cell Carcinoma Suspicion. Eur Urol. sept 
2018;74(3):257‑60.  
20.  Smaldone MC, Chen DY, Yu JQ, Plimack ER. Potential role of (124)I-girentuximab in the 
presurgical diagnosis of clear-cell renal cell cancer. Biologics. 2012;6:395‑407.  
21.  Tafreshi NK, Lloyd MC, Bui MM, Gillies RJ, Morse DL. Carbonic anhydrase IX as an imaging and 
therapeutic target for tumors and metastases. Subcell Biochem. 2014;75:221‑54.  
22.  Oosting SF, Brouwers AH, van Es SC, Nagengast WB, Oude Munnink TH, Lub-de Hooge MN, et al. 
89Zr-bevacizumab PET visualizes heterogeneous tracer accumulation in tumor lesions of renal 
cell carcinoma patients and differential effects of antiangiogenic treatment. J Nucl Med. janv 
2015;56(1):63‑9.  
23.  Stabin MG, Sparks RB, Crowe E. OLINDA/EXM: the second-generation personal computer 
software for internal dose assessment in nuclear medicine. J Nucl Med. juin 2005;46(6):1023‑7.  

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24.  Andersson M, Johansson L, Eckerman K, Mattsson S. IDAC-Dose 2.1, an internal dosimetry 
program for diagnostic nuclear medicine based on the ICRP adult reference voxel phantoms. 
EJNMMI Res. 3 nov 2017;7(1):88.  
25.  Menke-van der Houven van Oordt CW, McGeoch A, Bergstrom M, McSherry I, Smith DA, 
Cleveland M, et al. Immuno-PET Imaging to Assess Target Engagement: Experience from 89Zr-
Anti-HER3 mAb (GSK2849330) in Patients with Solid Tumors. J Nucl Med. juill 2019;60(7):902‑9.  
  
  
 
 
 
 

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16. 
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 
 
Appendix 7: Intravesical instillation procedure