Phase II Study of Preliminary Diagnostic Performance of [68Ga]-NeoBOMB1 in Adult Patients With Malignancies Known to Overexpress Gastrin Releasing Peptide Receptor (GRPR)
Phase: PHASE2
Conditions: Breast Cancer, Prostate Cancer, Colorectal Cancer, Non Small Cell Lung Cancer, Small Cell Lung Cancer
Sponsor: Advanced Accelerator Applications

A005D-E01-201 
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Study Protocol 
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Study Protocol 
Protocol Number 
A005D-E01-201 / NCT03724253
EudraCT Number 
2017-003432-37 
Investigational Product 
 [68Ga]-NeoBOMB1 50 µg, kit for radiopharmaceutical 
preparation 
Active substance 
NeoBOMB1 
Radiolabelled Imaging 
Product 
[68Ga]-NeoBOMB1 
Trial Phase 
Phase II 
Trial Title 
Phase II study of preliminary diagnostic performance of 
[68Ga]-NeoBOMB1 in adult patients with malignancies known 
to overexpress Gastrin Releasing Peptide Receptor 
Short Trial Title 
NeoFIND - [68Ga]-NeoBOMB1 imaging in patients with 
malignancies known to overexpress GRPR 
Version and Date 
v.3.0. dated 05 July 2018
Trial Sponsor 
Advanced Accelerator Applications 
The concepts and information contained herein or generated during the study 
are considered proprietary and shall not be disclosed in whole or in part without 
the expressed written consent of Advanced Accelerator Applications. 
This study is to be completed according to the guidelines of Good Clinical Practice 
(GCP) and conducted in full compliance with the World Medical Association 
Declaration of Helsinki and its most recent amendments. 

 
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SPONSOR SIGNATORY APPROVAL PAGE 
 
 
PROTOCOL TITLE: 
Phase II study of preliminary diagnostic performance of [68Ga]-NeoBOMB1 
in adult patients with malignancies known to overexpress Gastrin-Releasing 
Peptide Receptor. 
 
PROTOCOL NUMBER:  A005D-E01-201 
 
Signatures on this page denote approval of the study protocol outline by the respective Sponsor 
Department 
 
 
Role 
Name and contact 
Date & Signature 
 
, MD 
Advanced Accelerator Applications SA 
Tel: 
 
E-mail: 
 
 
 
 MD, PhD, DABT 
Advanced Accelerator Applications SA 
Tel: 
 
Cell: 
 
E-mail: 
 
 
 
 
 
, MSc Pharm 
Advanced Accelerator Applications SA 
Tel:  
 
Fax: 
 
Cell: 
 
E-mail:
 
 
 
 
 

 
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INVESTIGATOR ENDORSEMENT PAGE 
 
I agree to conduct the study as outlined in the protocol entitled “Phase II study of preliminary 
diagnostic performance of [68Ga]-NeoBOMB1 in adult patients with malignancies known to 
overexpress Gastrin-Releasing Peptide Receptor.” in accordance with the guidelines and all 
applicable government regulations. These guidelines and regulations include, but are not 
limited to:  
 
1. 
Permission to allow the Sponsor and the regulatory agencies to inspect study facilities 
and pertinent records at reasonable times and in a reasonable manner that ensures 
participant confidentiality.  If this study is to be inspected by a regulatory agency, the 
Sponsor should be notified as soon as possible; 
 
2. 
Submission of the proposed clinical investigation, including the protocol and the 
consent form to a duly constituted Ethic Committee (EC) as well as competent 
authorities for approval and acquisition of written approval prior to study conduct; 
 
3. 
Use of written informed consent that is obtained prior to study conduct and that 
contains all the elements of consent as specified in the federal regulations and has 
been previously approved by the Sponsor, the EC and the Competent Authority (CA); 
 
4. 
Submission of any proposed change in or deviation from the protocol to the EC to be 
approved by the Sponsor. Any proposed changes or deviations from the protocol may 
require that the informed consent also reflect such changes or deviations and that the 
revised informed consent be approved by the EC and competent authority; 
 
5. 
Documentation and explanation of individual protocol deviations on the appropriate 
case report form page or in letters to the Sponsor; 
 
6. 
Reports of serious adverse events to the Sponsor/CRO (Contract Research 
Organisation) within 24 hours by telephone and a written report of the serious adverse 
event within 72 hours after the Investigator’s initial receipt of the information; 
 
7. 
Reporting of Serious Adverse Events (SAE) according to ICH/GCP (International 
Conference Harmonization/ Good Clinical Practices) and regulator standards. SAE 
will be reported from the signing of the informed consent and followed until resolution 
or determined to be not clinically significant; 
 
8. 
Submission of timely progress reports to the EC and Sponsor at appropriate intervals 
on a schedule determined by the EC. 
 
Regulations require an Investigator to prepare and maintain adequate and accurate case 
histories designed to record all observations and other data (such as investigational product 
accountability) pertinent to the investigation on everyone enrolled in the study. These records 

 
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must be maintained by the Investigator for a minimum period of 15 years or a period of time 
determined by the Sponsor following the date a marketing application is approved for the 
indication for which it is being investigated, or, if no application is to be filed or if the application 
is not approved for such indication, a minimum of 15 years or a period of time determined by 
the Sponsor after the investigation is discontinued and the appropriate regulatory authorities 
are notified. 
 
In addition, I agree to provide all the information requested in the case report form in a manner 
to assure legibility and accuracy. To this end, I shall carefully follow the instructions for 
completing case report forms. 
 
I also agree that all information provided to me by the Sponsor, including protocols, case report 
forms, and verbal and written information, will be kept strictly confidential and confined to the 
clinical personnel involved in conducting the study. It is recognized that this information may 
be related in confidence to the EC/regulatory authorities. I also understand that reports of 
information about the study or its progress will not be provided to anyone who is not involved 
in the study other than to the Principal Investigator, or in confidence to the EC or to the legally 
constituted regulatory authorities. 
 
 
 
 
Principal Investigator Signature 
 
Date of Signature 
 
 
 

 
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Content 
SPONSOR SIGNATORY APPROVAL PAGE ........................................................................................ 2 
INVESTIGATOR ENDORSEMENT PAGE ............................................................................................. 3 
1 
Study Synopsis ............................................................................................................................... 12 
2 
Introduction ..................................................................................................................................... 20 
2.1 
Background............................................................................................................................ 20 
2.2 
Preclinical data ...................................................................................................................... 21 
2.3 
Clinical data ........................................................................................................................... 21 
2.3.1 
Clinical studies performed with Bombesin analogues ....................................................... 21 
2.3.2 
[68Ga]-NeoBOMB1 in GRPR-positive malignancies .......................................................... 25 
2.4 
Rationale and risks/benefits .................................................................................................. 27 
3 
Study design ................................................................................................................................... 28 
3.1 
Description of the study ......................................................................................................... 28 
3.2 
Study objectives .................................................................................................................... 30 
3.2.1 
Primary Study Objective .................................................................................................... 30 
3.2.2 
Secondary Study Objectives ............................................................................................. 30 
 
 31 
3.3 
Study Endpoints .................................................................................................................... 31 
3.3.1 
Primary Study Endpoint ..................................................................................................... 31 
3.3.2 
Secondary Study Endpoints .............................................................................................. 31 
 
 32 
3.4 
Study population / Selection of subjects ................................................................................ 32 
3.4.1 
Inclusion criteria ................................................................................................................. 32 
3.4.2 
Exclusion criteria................................................................................................................ 33 
3.4.3 
Patients recruitment ........................................................................................................... 33 
3.4.4 
Patient ID definition ........................................................................................................... 34 
3.4.5 
Withdrawal of trial subjects after trial start ......................................................................... 34 
3.4.6 
Closure of trial sites/Premature termination of the clinical trial ......................................... 35 
4 
Study procedures and schedule of assessments .......................................................................... 35 
4.1 
Study procedures .................................................................................................................. 35 
4.1.1 
Informed consent form ....................................................................................................... 36 
4.1.2 
Physical examinations ....................................................................................................... 36 
4.1.3 
Vital signs .......................................................................................................................... 36 
4.1.4 
ECG ................................................................................................................................... 36 
4.1.5 
Routine laboratory exams and pregnancy test .................................................................. 37 

 
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4.1.6 
Imaging .............................................................................................................................. 37 
4.1.7 
Biodistribution and dosimetry ............................................................................................ 41 
4.1.8 
Assessment of GRPR expression ..................................................................................... 42 
4.1.9 
Adverse Events and Concomitant Medications ................................................................. 42 
4.2 
Schedule of assessments ...................................................................................................... 42 
4.2.1 
Screening period (Visit 0, days –28 to – 1) ....................................................................... 42 
4.2.2 
Injection/PET Imaging day (Day 1/Visit 1) ......................................................................... 43 
4.3 
Safety follow-up visits (Day 2/Visit 2, Day 7/Visit 3 and Day 14/Visit 4)................................ 44 
4.4 
Optional routine clinical disease follow-up ............................................................................ 44 
4.5 
Visit and Assessment Schedule ............................................................................................ 44 
5 
Study medication ............................................................................................................................ 48 
5.1 
Name and description of Investigational Medicinal Product .................................................. 48 
5.2 
IMP administration ................................................................................................................. 48 
5.3 
Dose modifications ................................................................................................................ 49 
5.4 
Concomitant medication ........................................................................................................ 49 
5.5 
Labelling ................................................................................................................................ 49 
5.6 
Handling and storage of IMP at the Site and IMP Accountability .......................................... 50 
5.7 
Subject compliance ............................................................................................................... 51 
6 
Safety Definitions and Reporting Requirements ............................................................................ 51 
6.1 
Adverse Events (AEs) ........................................................................................................... 51 
6.2 
Serious Adverse Events (SAEs) ............................................................................................ 51 
6.3 
Adverse Drug Reaction (ADR) & Unexpected Adverse Drug Reaction ................................ 52 
6.4 
Suspected Unexpected Serious Adverse Reaction (SUSAR) ............................................... 52 
6.5 
Pregnancy .............................................................................................................................. 53 
6.6 
Severity of adverse events / Grading .................................................................................... 53 
6.7 
Relationship to study drug ..................................................................................................... 54 
6.8 
Reporting procedures for AEs ............................................................................................... 54 
6.9 
Reporting procedures for SAEs ............................................................................................. 55 
6.10 
Reporting to the competent authorities and IRB/IEC ............................................................ 56 
6.11 
Adverse Event Reporting Period ........................................................................................... 56 
6.12 
Annual Safety Report ............................................................................................................ 57 
7 
Statistical considerations ................................................................................................................ 57 
7.1 
Sample Size & Randomization .............................................................................................. 57 
7.2 
Statistical Design, Method and analytical Procedures and Definition of Populations ........... 58 
7.3 
Efficacy Analysis .................................................................................................................... 58 
7.4 
Safety Analysis ...................................................................................................................... 60 

 
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7.5 
The treatment of missing, unused or spurious Data, including Drop-outs and Withdrawals 61 
8 
Documentation ............................................................................................................................... 61 
8.1 
Recording of Data .................................................................................................................. 61 
8.2 
Trial Master File ..................................................................................................................... 62 
8.3 
Investigator Site File .............................................................................................................. 62 
8.4 
Storage of Data ..................................................................................................................... 62 
8.4.1 
Storage Duties of the Sponsor .......................................................................................... 62 
8.4.2 
Storage Duties of the Investigator ..................................................................................... 62 
9 
Quality Control and Quality Assurance .......................................................................................... 62 
9.1 
Training .................................................................................................................................. 63 
9.2 
Clinical Monitoring ................................................................................................................. 63 
9.3 
Auditing .................................................................................................................................. 63 
10 
Reporting ................................................................................................................................... 64 
10.1 
Final Study Report ................................................................................................................. 64 
10.2 
Publication/Data sharing Policy ............................................................................................. 64 
11 
Ethical and Regulatory Aspects................................................................................................. 64 
11.1 
Good Clinical Practice and Declaration of Helsinki ............................................................... 64 
11.2 
Approval of the Study ........................................................................................................ 6564 
11.3 
Insurance ............................................................................................................................... 65 
11.4 
Confidentiality ........................................................................................................................ 65 
12 
Amendments.............................................................................................................................. 65 
13 
References ................................................................................................................................ 66 
14 
Supplements/Appendices .......................................................................................................... 69 
14.1 
Appendix 1: Toxicity Grading Scale vaccine in clinical trials ................................................. 69 
 
 
 
 
 

 
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List of abbreviations 
 
AE 
AC 
ADR 
BC 
CA 
CNS 
e-CRF 
CRO 
CRP 
CT 
DSUR 
EC 
ECG 
ECOG 
EGF 
EGFR 
eGFR 
ER 
FAS 
FDA 
[18F]-FDG 
GCP 
GIST 
GMP 
GRP 
GRPR 
Hb 
HCl 
Adverse Event 
Activity Curves  
Adverse Drug Reaction 
Breast Cancer 
Competent Authority 
Central Nervous System 
Electronic Case Report Form 
Clinical Research Organization 
C-Reactive Protein 
Computed Tomography  
Drug Safety Update Report 
Ethic Commitee 
Electrocardiography 
Eastern Cooperative Oncology  
Epidermal Growth Factor 
Epidermal Growth Factor Receptor 
estimated Glomerular Filtration Rate  
Estrogen receptor 
Full Analysis Set 
Food and Drug Administration 
18-fluorodeoxyglucose 
Good Clinical Practice 
Gastro Intestinal Stromal Tumour  
Good Manufacturing Practice  
Gastrin-Releasing Peptide 
Gastrin-Releasing Peptide Receptor 
Hemoglobin 
Hydrogen Chloride  

 
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HPLC 
HR 
ICF 
ICH 
ICRP 
IEC 
IHC 
IMP 
IRB 
ISF 
ITLC 
ITT 
LN 
LPLV 
MBq 
MIRD 
MedDRA 
MRI 
NCI 
NMB 
NOAEL 
NSCLC 
PC 
PET 
p.i. 
PI 
PK 
PP 
PT 
PTT 
High-Performance Liquid Chromatography 
Heart Rate 
Informed Consent Form 
International Conference on Harmonization 
International Commission on Radiological Protection  
Independent Ethics Committee 
Immunohistochemistry 
Investigational Medicinal Product 
Institutional Review Board 
Investigator Site File  
Instant Thin Layer Chromatography 
Intention To Treat 
Lymph Node 
Last Patient Last Visit 
Mega Becquerel 
Medical Internal Radiation Dose 
Medical Dictionary For Regulatory Activities 
Magnetic Resonance Imaging 
National Cancer Institute 
Neuromedin B  
No Observed Adverse Effect Level 
Non–Small Cell Lung Cancer 
Prostate Cancer 
Positron Emission Tomography 
Post injection 
Principal Investigator 
Pharmacokinetics  
Per Protocol 
Prothrombin Time 
Partial Thromboplastin Time 

 
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PV 
PT 
QA 
QC 
QTc 
RBC 
RCP 
ROI 
RR 
SAE 
SAP 
SD 
SOC 
SOP 
mSv 
SUSAR 
SUV 
TAC 
TBR 
TKI 
TMF 
WBC 
WHO 
VOI 
Pharmacovigilance 
Preferred Term  
Quality Assurance 
Quality Control 
frequency-corrected QT-time  
Red Blood Cell 
Radiochemical Purity 
Region of Interest 
Respiratory Rate 
Serious Adverse Event 
Statistical Analysis Plan 
Standard Deviation 
System Organ Class  
Standard Operating Procedure 
milliSievert 
Suspected Unexpected Adverse Reaction 
Standardized Uptake Value  
Time Activity Curve 
Target to background ratio 
Tyrosine-Kinase Inhibitor 
Trial Master File 
White Blood Cell 
World Health Organization 
Volume Of Interest 
 
 
 
 

 
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Definitions 
 
• 
Pre-screening: 
The pre-screening is the period before the signature of the Informed Consent Form (ICF). 
 
• 
Screening: 
The screening period starts at the time of signature of ICF and ends on the day of IMP injection.  
 
• 
Enrollment: 
A subject is enrolled when he/she is administered with the Investigational Medicinal Product 
(IMP). 
 
• 
IMP phase: 
The IMP phase starts when IMP is administered to a subject, i.e. if a subject has entered the 
IMP phase, it means this subject has been injected with [68Ga]-NeoBOMB1. 
 
• 
Screening failure: 
A screening failure occurs when a subject who has signed the ICF (i.e. screened/enrolled 
subject) does not enter the IMP phase (i.e. injected subject). 
 
 

 
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1 Study Synopsis 
 
Clinical Study [68Ga]-NeoBOMB1 – EudraCT Number: 2017-003432-37 
Version date 
July, 05th , 2018 
 
Version 3.0 
 
Study number 
 A005D-E01-201 
Clinical phase: II 
 
 
Investigational 
Medicinal Product  
[68Ga]-NeoBOMB1 50 µg, kit for radiopharmaceutical preparation 
Title of the study 
Phase II study of preliminary diagnostic performance of [68Ga]-NeoBOMB1 
in adult patients with malignancies known to overexpress Gastrin Releasing 
Peptide Receptor. 
Study centres 
Multi-center study 
Sponsor 
Advanced Accelerator Applications 
Potential Indication Diagnosis and or monitoring of tumours known to overexpress GRPR. 
Rationale 
GRP is a bombesin-like peptide growth factor implicated in the regulation of 
numerous central and peripheral functions. By binding to a GRP extracellular 
receptor (GRPR), it activates an intracellular G-protein that triggers further 
chain reactions. Beside its physiological widespread role, GRP has been 
demonstrated to be a potent mitogen for normal and neoplastic tissues and 
may be involved in growth dysregulation and carcinogenesis.  
In fact, upregulation of GRP/GRPR has been reported in several cancers, 
including breast, prostate, colon, lung (small cell and non-small cell), 
stomach, pancreas, uterus, ovaries, head and neck squamous cell cancer 
and in various central nervous system malignancies.  
For instance, GRPR expression has been investigated in primary and 
metastatic breast cancer among different molecular subtypes. GRPR 
overexpression was most strongly associated with estrogen receptor (ER) 
positivity and found in over 75% of the primary tumour samples and in over 
90% of their metastatic lymph nodes. 
In parallel, a massive GRP receptor overexpression has been demonstrated 
in prostate tissues that are already neoplastic or in the process of malignant 
transformation (i.e. prostatic intraepithelial neoplasias). In this specific case, 
GRP receptors have been thought of as markers for early molecular events 
in prostate carcinogenesis and useful in differentiating prostate hyperplasia 
from prostate neoplasia.  
In the lung, GRP has been found in the pulmonary neuroendocrine cells and 
is responsible for lung development and maturation. Nevertheless, GRP has 
also been reported in relation to growth dysregulation and carcinogenesis on 
non–small cell lung cancer (NSCLC) proliferation. In fact, increased levels of 

 
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GRP have led to increased release of pro-ligands for epidermal growth factor 
receptor (EGFR) with subsequent activation of EGF and mitogen-activated 
protein kinase downstream pathways.  
Presence of GRP and/or expression GRPR have also been investigated in 
colorectal cancer samples (primary tumour, lymph nodes and metastatic 
lesions) where over 80% samples expressed GRP/GRPR as opposed to 
adjacent normal healthy epithelium. 
Overall, the literature accounts with a growing body of evidence suggesting 
that GRPR might be a valuable target.  
Peptide receptor agonists have long been the ligands of choice for tracer 
development and utilization in nuclear medicine thanks to their high 
radioactive accumulation inside the target cells after receptor-radioligand 
complex internalization. However, GRPR antagonists have been compared 
to GRPR agonists and showed greater tumour uptake and better image 
contrast. Furthermore, GRPR antagonists allow for a safer clinical use, since 
no acute biological adverse effects are expected.  
The Sponsor has therefore designed the current protocol to establish 
whether the ligand NeoBOMB1, a high affinity antagonist for GRPR, 
radiolabelled with a well-established PET isotope, Gallium-68 (68Ga) is a 
suitable radiotracer for in vivo detection of GRPR-expressing malignancies, 
currently focusing on breast, prostate, lung (small cell and non-small cell) and 
colon-rectum.  
Objectives 
Primary Objective 
• 
To characterize preliminary targeting properties of [68Ga]-
NeoBOMB1 in patients with malignancies known to overexpress 
GRPR. 
 
Secondary objectives 
• 
To assess safety and tolerability of a single diagnostic dose of [68Ga]-
NeoBOMB1 administered as an intravenous bolus injection. 
• 
To 
assess 
the 
bio-distribution, 
pharmacokinetics, 
radiation 
dosimetry, and absorbed doses in critical organs for [68Ga]-
NeoBOMB1 in a limited set of patients. 
• 
To establish the optimal threshold, expressed as Standardized 
Uptake Value (SUV), to discriminate Positron Emission Tomography 
(PET) imaging positive results from negative ones. 
• 
To estimate the [68Ga]-NeoBOMB1 PET imaging performance lesion-
based and patient-based relative to a comparable standard imaging 
practice (eg PET, CT) according to the tumour type. 
• 
To estimate the [68Ga]-NeoBOMB1 PET diagnostic performance 
lesion-based and patient-based relative to the GRPR histopathology 

 
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findings (e.g. IHC) 
 
 
Study design 
This is a Phase II, multi-center, open label, single dose study in patients with 
tumour types known to overexpress GRPR, including breast, prostate, 
colorectal, non-small cell lung (NSCL) and small-cell lung (SCL) cancer.  
Population will be divided into two groups: 
• 
a Phase-II dosimetry group, accounting with 10 patients (splitted 
into breast cancer: n=5 female patients and prostate cancer: n=5 
male patients) who will undergo several assessments to confirm 
previous data on tracer bio-distribution, radiation dosimetry, 
residence time for critical organs, and absorbed dose critical organs 
for [68Ga]-NeoBOMB1. Venous whole blood and urine samples will 
be collected for activity-based pharmacokinetics characterization; 
• 
a Phase-II non-dosimetry group, accounting with 40 patients 
splitted into : 
✓ Breast cancer: n=5  
✓ Prostate cancer: n=5  
✓ Colorectal cancer: n=10.  
✓ NSCLC: n=10  
✓ SCLC: n=10  
Patients included in the non-dosimetry group will undergo one early and one 
late whole-body PET-imaging acquisition, with no blood and urine sampling. 
Only prostate tumour patients will undergo an additional early 5-min static 
PET scan to better assess lymph node metastases (if applicable). 
GRPR expression must be assessed while the study is ongoing within 4 
weeks after IMP injection by Immunohistochemistry staining from archival 
or recent biopsy specimens (not older than 6 months prior to IMP injection).  
The objectives of the study will be applicable for the whole study population 
with the exception of the secondary objective relative to the biodistribution 
and dosimetry that will be applicable only for the dosimetry group. 
PET Imaging Data 
acquisition 
The subjects enrolled in the dosimetry group will undergo 4 15-min static 
whole-body PET scans at 15 min, 1h±15 min, 2h±15 min and at 4h±30 min 
post injection (p.i.) to determine absorbed doses to normal organs and to 
target tumour lesions. Regions of Interest (ROIs) or Volumes of Interest 
(VOIs) will be drawn on the late whole-body PET images over the critical 
organs and tumour lesions to generate tissue time-activity curves (TACs), 
calculate the tumour-background ratio and assess the radioactivity residence 
times.  
To determine blood activity curves, venous whole blood samples will be 
withdrawn (around 0, 5, 10, 20, 30, 60 min, 2 h and 3-4 h p.i.) and assessed 

 
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via -counter for radioactivity measurements. Urine samples from 0-2 h and 
from 2-4 h p.i. will be collected and assessed via -counter for radioactivity 
measurements to complete dosimetry and biodistribution assessments. 
Urine samples will be saved, frozen for further metabolite assessments, at 
the Sponsor’s decision.  
The subjects enrolled in the Phase II non-dosimetry group will undergo 
whole-body PET acquisitions at 1h30±30min and at 2h30±30min, likely to be 
a 15-min static PET for all tumour-types combined with a 5-min-static early-
PET for prostate cancer. 
CT Imaging Data 
Acquisition 
For all patients a low-dose CT will be combined to PET imaging. 
Data analysis, 
biodistribution and 
dosimetry 
 
Dosimetry group: 
ROIs/VOIs for critical organs and tumour lesions will be drawn using the 
acquired static PET images resulting in tissue TACs with quantitative 
fractions of administered activity. ROIs/VOIs will be drawn over these organs 
to determine relative radiotracer uptake calculated as a percentage of the 
injected dose per gram of tissue (%ID/g). Tissue TACs will be generated from 
the amount of radioactivity in one given tissue considering renal excretion 
activity.   
Tissue TACs will be fitted to mono- and bi-exponential curves to yield 
cumulative activities and residence times will be calculated.  
Dosimetry calculations will be issued from the analyses of organs receiving 
the highest dose, identified visually. Urine samples from 0-2h and from 2-4h 
post-injection will be collected to complete dosimetry and biodistribution 
assessments.  
The 
absorbed 
dose (μGy/MBq) 
will 
be 
transformed 
into 
formal 
biological equivalent dose for radiation exposure (μSv/MBq) to finally yield 
an effective radiation dose, a factor between others that could help providing 
an estimation of total danger to the whole organism. 
 
All patients: 
Maximum standardized uptake values (SUVmax) will be used to determine the 
tumour lesions, defined as focal areas of abnormal uptake featuring greater 
SUVmax than that of surrounding tissue. The imaging time points 
characterized by the greatest number of lesions will be identified via 
qualitative visual analysis. Similarly, the greatest SUV values will be 
determined for each lesion on all scans via semi-quantitative analysis. 
Malignant-like lesions compatible per tumour type and localisation will be 
semi-quantified and expressed as SUVmean and SUVmax. All lesions will be 
counted and analyzed by measuring SUVmean and SUVmax and relative 
background.  
Clinical assessment (surgery, imaging or physical examination) during 3 
months after IMP injection will be collected if available for patients to 

 
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correlate the focal uptake of [68Ga]-NeoBOMB1 PET which was not possible 
be matched to morphological lesions on CT/MRI. 
Safety 
Safety 
assessments 
including 
physical 
examination, 
vital 
signs, 
Electrocardiogram 
(ECG) 
with 
frequency-corrected 
QT-time 
(QTc) 
assessment, routine blood analysis and urinalysis will be performed prior to 
[68Ga]-NeoBOMB1 administration on all subjects.  
Dosimetry group: twelve-lead ECG readings and vital signs will be checked 
pre-dose, immediately after the radiotracer administration, at 30 min, after 
the last whole-body scan (around 4h) and during the FU visits scheduled at 
Day 2 (24h p.i.), Day 7±1, and Day 14±2 for physical examination, routine 
blood analysis, urinalysis, vital signs and ECG. 
Non-dosimetry group: twelve-lead ECG readings and vital signs will be 
checked at pre-dose and at 30 min after the administration. At Day 2, the FU 
visit will be a phone call to assess potential adverse events, allergic reactions 
and concomitant treatments. The FU visits of Day 7±1 and Day 14±2 
account for physical examination, routine blood analysis, urinalysis, vital 
signs and ECG. Visit at Day 7±1 is optional and can be replaced by a phone 
call to only assess potential adverse events, allergic reactions and 
concomitant treatments. 
The emergence of any Adverse Event (AE) and Serious Adverse Event 
(SAE) will be monitored and recorded during trial conduct. Adverse events 
will be graded per the Toxicity Grading Scale in vaccine clinical trials. 
Tracer 
NeoBOMB1 will be radiolabelled locally following a predefined procedure 
using a solution of 68Ga in hydrochloric acid (HCl) provided by a 68Ge/68Ga 
generator to obtain [68Ga]-NeoBOMB1 as radiolabelling imaging product for 
intravenous injection. 
The dose of [68Ga]-NeoBOMB1 to be injected is 3MBq/kg ±10%, no less than 
150 MBq and no more than 250 MBq. This amount of radioactivity is 
sufficient for Quality Control (QC) testing and quality imaging with [68Ga]-
NeoBOMB1. 
[68Ga]-NeoBOMB1 will be administered according to applicable regulation 
(including local regulations, International Commission on Radiological 
Protection (ICRP) Publication 62 and Radiation protection 99). 
Planned number of 
subjects 
Fifty patients bearing malignancies known to overexpress GRPR originating 
from either breast, prostate, lung (small-cell and non-small cell) or colon-
rectum will be enrolled. Population will be divided into 2 groups: the 
dosimetry group will include 5 patients with breast cancer and 5 patients with 
prostate cancer, who will undergo further assessments for dosimetry 
calculations. 
The non-dosimetry group will include 40 patients. Patients will be splitted into 
: 
✓ Breast cancer: n=5  

 
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✓ Prostate cancer: n=5  
✓ Colorectal cancer: n=10.  
✓ NSCLC: n=10  
✓ SCLC: n=10  
Inclusion and 
exclusion criteria  
Main Inclusion Criteria 
 
1. Subjects must be at least 18 years of age 
2. Subjects must have signed and dated an informed consent prior to 
any study-specific procedures. 
3. Subjects with histologically-confirmed tumour, for whom a less than 
6-month-old biopsy has been performed. 
4. Dosimetry group:  
• 
Luminal breast cancer 
• 
Adenocarcinoma of the prostate 
5. Non-dosimetry group:  
• 
Luminal breast cancer 
• 
Adenocarcinoma of the prostate 
• 
Small-cell lung cancer 
• 
Non-small cell lung cancer 
• 
Colorectal carcinoma 
6. At least one malignant lesion detected via functional or morphological 
imaging (PET combined to appropriate tracer according to tumour 
type, CT, MRI) within 3 months prior to the administration of [68Ga]-
NeoBOMB1. 
7.  The Eastern Cooperative Oncology (ECOG) performance status 0-
2. 
8. Subjects must agree to use highly effective methods of contraception 
(female partners of male participants should use highly effective 
methods of contraception) during the trial. 
 
Main Exclusion Criteria 
1. Renal insufficiency or an estimated Glomerular Filtration Rate 
(eGFR) <50 ml/min/1.73m2. 
2. Haematological toxicity grade > 2 (Toxicity Grading Scale in vaccine 
clinical trials) 
3. Participation in any other investigational trial within 30 days of study 
entry. 
4. Subjects with positive pregnancy test (Urine dipstick), and/or 
currently breast-feeding  
5. Concurrent severe illness or clinically relevant trauma within 2 weeks 
before the administration of the investigational product that might 
preclude study completion or interfere with study results. 
6. Concurrent bladder outflow obstruction or unmanageable urinary 
incontinence. 

 
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7. Known or expected hypersensitivity to 68Gallium, NeoBOMB1, or any 
excipient present in [68Ga]-NeoBOMB1. 
8. Any condition that precludes raised arms position 
9. Prior administration of a radiopharmaceutical within a period 
corresponding to 8 half-lives of the radionuclide. 
10. History of somatic or psychiatric disease/condition that may interfere 
with the objectives and assessments of the study. 
Study duration and 
Assessments  
The study will have a duration of approximately 6 weeks, with a pre-injection 
phase of 4 weeks, including the screening/baseline assessment period, the 
injection and PET visit on Day 1, 3 safety follow-up visits post-administration 
of investigational drug on Day 2, Day 7±1 and Day 14±2. If available, data 
generated from routine clinical disease follow-up assessments within 3 
months from IMP injection will be collected. 
The study assessments are described in the Visits Schedules and 
assessment, section 4.5. 
Study periods 
A) The Screening period will last 28 days (Day -28 to -1) or less per 
subject and includes the Screening Visit to obtain informed consent 
and establish protocol eligibility. 
B) The injection and PET day is [68Ga]-NeoBOMB1 administration day 
(Day 1) and differs according to groups. For the dosimetry group, it 
includes 7 time-points: pre-dose, 0-5 min, 5-15 min, 30 min, 1h, 2h, 3-
4h p.i.. For the non-dosimetry group, it includes 4 time-points: pre-
dose, injection (0-5 min), 1h30±30min p.i. and 2h30±30 min p.i.  
C) The safety follow-up period lasts for 14 days from PET day. It includes 
FU visits on Day 2, Day 7±1, and Day 14±2 for all subjects. 
D) The optional routine clinical follow-up will start on D14±2 follow-up 
visit and will last up to 3 months from IMP injection according to clinical 
disease assessment.  
Statistical methods 
 
All statistical analyses will be primarily descriptive in nature and will include 
summaries and graphical presentations of data.  All data presentations will 
be presented by the overall population but may also be repeated split by 
tumour type where relevant.  Some presentations will also be repeated split 
by whether or not the patient was found to have tumours bearing GRPR 
expression according to cytology and/or histopathology findings. 
The preliminary targeting properties of [68Ga]-NeoBOMB1 will be assessed 
by summaries of number and location of lesions identified by PET, SUV 
values per lesion, tumour background ratio of [68Ga]-NeoBOMB1 and the 
percentage of injected dose reaching the target presented split by GRPR 
positive and negative patients.  Tumour uptake will be evaluated by Standard 
Uptake Value. SUVmean and SUVmax will be determined and summarized 
descriptively. 
Adverse events will be listed on an individual basis and summarized by 
System Organ Class and Preferred term including relationship and severity.  

 
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Clinical laboratory parameters, vital signs, and ECG parameters will be 
summarized and presented graphically as observed values and changes 
form baseline at each measuring time.  Clinical laboratory parameters will 
also be analysed in terms of tabulations of values to within, below or above 
normal ranges provided by the laboratory of each site.   
 
Descriptive statistics and graphical presentations will be produced for bio-
distribution, radiation dosimetry data as appropriate. 
Number of observed tumour lesions and localization in PET/CT will be 
compared to number of observed lesions and localization in a comparable 
conventional imaging by GRPR positive and negative patients.  Positive and 
negative lesions by the two imaging techniques will be cross tabulated overall 
and by localization area on a lesion level and a patient level and overall, 
positive and negative sensitivity agreement calculations and tests of 
association will be performed where appropriate overall and split by GRPR 
positive and negative patients.  This will also be repeated splitting by primary 
tumour type of patients in the trial. The preliminary diagnostic performance 
of [68Ga]-NeoBOMB1 relative to cytology and/or histopathology findings 
from archival and/or recent biopsy specimens will be assessed primarily on 
a patient level, but also on a lesion level for lesions with associated biopsy 
data available.  Sensitivity and specificity calculations will be performed by 
cross tabulating GRPR positive or negative patients according to cytology 
data with whether those patients had lesions detected by PET imaging.  
Appropriate tests of association may also be performed if relevant. 
 
 
 
 

 
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2 Introduction 
 
2.1 Background  
 
Gastrin-releasing peptide (GRP), a bombesin-like peptide growth factor, regulates numerous 
functions of the gastrointestinal and central nervous systems, including release of 
gastrointestinal hormones, smooth muscle cell contraction, and epithelial cell proliferation. It is 
a potent mitogen for physiologic and neoplastic tissues, and it may be involved in growth 
dysregulation and carcinogenesis.  
The effects of GRP are primarily mediated through binding to its receptor, the GRP receptor 
(GRPR), a G protein–coupled receptor originally isolated from a small cell lung cancer cell line. 
Upregulation of the pathway of GRP/GRPR has been reported in several cancers, including 
breast, prostate, uterus, ovaries, colon, pancreas, stomach, lung (small and non-small cell), 
head and neck squamous cell cancer and in various cerebral and neural tumours. 
In breast cancer, GRPR overexpression can reach very high density according to tumour type 
(e.g. 70-90 % expression in ductal breast cancer specimens) [1]. GRPR are highly 
overexpressed in prostate cancer where studies in human prostate cancer cell-lines and 
xenograft models showed both high affinity (nM level) and high tumour uptake (%ID/g) but the 
relative expression of GRPR across evolving disease setting from early to late stage has not 
been fully elucidated yet [2]. In colorectal patients, presence of GRP and expression of GRPR 
have been determined by immunohistochemistry in randomly selected colon cancers samples, 
including LN and metastatic lesions. Over 80% of samples aberrantly expressed either GRP or 
GRPR, and over 60% expressing both GRP and GRPR, whereas expression was not observed 
in adjacent normal healthy epithelium [3].  
GRP is physiologically present in pulmonary neuroendocrine cells and plays a role in 
stimulating lung development and maturation. However, it seems to also be involved in growth 
dysregulation and carcinogenesis. Stimulation of GRP leads to increasing the release of 
epidermal growth factor receptor (EGFR) ligands with subsequent activation of EGFR and 
mitogen-activated protein kinase downstream pathways. Using non–small cell lung cancer 
(NSCLC) cell lines it has been confirmed that EGF and GRP both stimulate NSCLC 
proliferation, and inhibition of either EGFR or GRPR resulted in cell death [4].  
 
In nuclear medicine, peptide receptor agonists have long been the ligands of choice for tracer 
development and utilization. The rationale behind the use of agonist-based constructs laid on 
to receptor-radioligand complex internalization enabling the high accumulation of radioactivity 
inside the target cells. In case of radiometal-labelled peptides, the efficient receptor-mediated 
endocytosis in response to agonist stimulation provides high in vivo radioactivity uptake in 
targeted tissues, a crucial prerequisite for optimal imaging of malignancies. However, a 
paradigm shift occurred when receptor-selective peptide antagonists showed preferable 
biodistribution, including considerably greater in vivo tumour uptake, compared with highly 
potent agonists. A further advantage displayed by GRPR antagonists is a safer clinical use, not 
so much at tracer doses for the current diagnostic point of view, but in view of greater doses for 
potential therapeutic purposes, as the use of antagonists does not foresee acute biological 
adverse effects [5].   

 
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The Sponsor has therefore designed the current protocol to establish whether the ligand 
NeoBOMB1, a high affinity antagonist for GRPR, radiolabelled with a well-established PET 
isotope, Gallium-68 (68Ga) is a suitable radiotracer for in vivo detection of GRPR-expressing 
malignancies, currently focusing on breast, prostate, lung (small cell and non-small cell) and 
colon-rectum.  
 
 
2.2 Preclinical data 
 
Bombesin was first isolated from the European frog Bombina bombina and was demonstrated 
to mimic the mammalian gastrin-releasing peptide (GRP) and neuromedin B (NMB)[6]. 
In non-clinical models, [68Ga]-NeoBOMB1 have shown high affinity to the GRPR expressed in 
breast, prostate, and Gastro Intestinal Stromal Tumour (GIST), as well as a low degree of 
internalization upon binding to the specific receptor. The ability of the radiolabelled peptide to 
target the GRPR expressing tumour has been confirmed in in vivo imaging studies in both 
prostate cancer and GIST models. 
 
 
2.3 Clinical data 
 
2.3.1 Clinical studies performed with Bombesin analogues 
 
Various bombesin-analogs have been studied in several entities, including both agonists and 
antagonists. The following summary tables (Table 1, 2, 3) provide the reference to each study. 
 
Table 1: Studies with in-human application of bombesin and its analogs in prostate cancer. 
Bombesin 
analogue 
Indication 
Dose 
Summary of Results 
[68Ga]-NeoBOMB1 
(antagonist) 
Prostate 
adenocarcinoma 
60-339 MBq 
First in man study – compassionate 
use program. Good tolerability, 
good sensitivity: visualization of 
liver micrometastatis and lymph-
node metastases down to 5 mm in 
size (n=4). [7] See protocol section 
2.3.2 
[68Ga]-SB3* 
(antagonist) 
Advanced 
prostate 
cancer 
(breast 
cancer 
also included) with 
progressing 
disease 
and 
history of previous 
therapy, including 
hormonal. 
283.91±91 
MBq 
23±0.7 
nmol 
(~35 µg) 
17 pts (9 PC + 8 BC): 5 out of 9 
(~55%) prostate cancer patients 
showed specific uptake. [8]   

 
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18F-BAY-86-4367 
(antagonist) 
Primary 
and 
recurrent prostate 
cancer 
302±11 MBq 
 
First in man study. PK/dosimetry in 
patients was good. Positive PET 
images in 3/5 with primary disease 
and 2/5 with biochemical relapse 
(n=10). [9] 
64Cu-CB-TE2A-
AR06 
(antagonist) 
newly diagnosed 
prostate 
cancer 
(T1c-T2b, GS 6-7) 
without 
prior 
therapy 
184±51 MBq 
14±4 µg 
Phase I study. PK/dosimetry was 
ok. Three out of 4 tumours were 
visualized with high contrast. [10] 
[68Ga]-BAY-86-
7548  
(also called RM2) 
(antagonist) 
histologically 
confirmed 
prostate 
adenocarcinoma 
or 
recurrent 
prostate cancer 
147 
MBq 
(median dose) 
~20 µg 
 
First 
in 
man 
study 
(n=14): 
sensitivity, specificity, and accuracy 
of 88%, 81% and 83%, respectively, 
for detection of primary PCa and 
sensitivity of 70% for metastatic LNs 
(histology as gold standard). [11] 
biochemically 
recurrent prostate 
cancer 
na 
Pilot comparison of ⁶⁸Ga-RM2 and 
⁶⁸Ga-PSMA-11 PET (n=7). ⁶⁸Ga-
PSMA-11 
had 
the 
highest 
physiologic uptake in the salivary 
glands and small bowel, with 
hepatobiliary and renal clearance, 
whereas ⁶⁸Ga-RM2 had the highest 
physiologic uptake in the pancreas, 
with renal clearance. ⁶⁸Ga-PSMA-
11 localized in a lymph node and 
seminal vesicle in a patient with no 
abnormal 
⁶⁸Ga-RM2 
uptake. 
Abdominal periaortic lymph nodes 
were more easily visualized by 
⁶⁸Ga-RM2 in two patients because 
of 
lack 
of 
interference 
by 
radioactivity in the small intestine. 
[12] 
99mTc-HABBN  
(agonist) 
biopsy-proven 
prostate cancer  
549–688 MBq 
SPECT/CT results were negative 
(most likely due to metabolic 
instability of the compound). GRPR 
expression confirmed by IHC. (n=8) 
[13] 
99mTc-[Leu13] 
BN 
(agonist) 
Suspected 
or 
proven 
prostate 
cancer  
185 MBq 
Positive SPECT scans obtained in 
all 8 patients with cancer (total of 10 
examined, 2 with benign adenoma). 
Invasion of pelvic LNs shown in 3 
cases (confirmed at surgery). [14] 
99mTc-RP527 
(agonist) 
Metastasized 
prostate cancer 
555 MBq 
First in man study with bombesin 
analogue including 4 patients with 
metastasized PC. Specific uptake 
observed in 1 out of 4. [15] 

 
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[68Ga]-RM1 
biopsy-proven 
prostate cancer 
111-142 MBq 
Pre-surgical 
newly 
diagnosed 
prostate cancer patients (n=7). High 
physiologic uptake in the pancreas 
and quick renal clearance. High and 
specific uptake in primary cancer 
lesions was found. The SUVmean 
and SUVmax of tumour region is 
4.22±1.33 and 4.64±2.53. Median 
tumour to background ratios was 
15.29 (9.27-26.42). [16] 
 
 
Table 2: Studies with in-human application of bombesin and its analogs in breast cancer. 
Bombesin 
analogue 
Indication 
Dose 
Summary of Results 
 [68Ga]-BAY-86-
7548  
(also called RM2) 
(antagonist) 
biopsy-proven 
primary 
breast 
carcinoma 
118 – 213 MBq 
(26 – 56 µg of 
peptide) 
High contrast in 73% examined 
breast cancer patients (n=15). 
Sensitivity of 93% for ER-positive 
tumours, upstaging in 47% of 
patients. [17] 
[68Ga]-SB3 
(antagonist) 
Advanced 
breast 
cancer 
(prostate 
cancer 
also 
included) 
with 
progressing 
disease and history 
of previous therapy 
283.91±91 
MBq 
23±0.7 
nmol 
(~35 µg) 
Mixed patients with prostate (n=9) 
and breast (n=8) cancer: 4 out of 8 
breast cancer patients showed 
specific uptake. [8] 
 
99mTc-Bombesin 
analogue  
(not specified) 
Suspicious palpable 
breast lesions (with 
no 
definitive 
diagnosis in other 
imaging 
procedures) 
370–444 MBq 
SPECT/CT scan findings were 
positive 
in 
19/33 
patients. 
Pathologic examination confirmed 
breast carcinoma in 12 patients with 
positive scan. Sensitivity (100%); 
specificity 
(66.1%); 
negative 
(100%) 
and 
positive 
(63%) 
predictive values; accuracy (76%). 
[18] 
99mTc-
EDDA/HYNIC-
[Lys3]-BBN  
(agonist) 
Early stage breast 
cancer and healthy 
volunteers. 
na 
Rapid blood clearance with mainly 
renal excretion. Good dosimetry. 
Well-differentiated concentration of 
tracer in cancer mammary tissue. 
[19] 
99mTc-RP527  
(agonist) 
Clinical 
diagnosis 
suggestive of breast 
carcinoma 
(n=9) 
and 
tamoxifen-
resistant 
bone-
metastasized 
~555 MBq 
(max 3ng/kg) 
Tracer uptake evident in the primary 
tumour in 8 out of 9 pts (88%) and 
in involved lymph nodes (confirmed 
by IHC). In the 5 patients with 
tamoxifen-resistant 
osseous 
disease, none (0/5) of the known 

 
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breast 
carcinoma 
(n=5) 
sites of osseous involvement were 
positive. [20] 
99mTc-[Leu13] BN 
(agonist) 
breast cancers (T1b 
and T1c) 
185-296 MBq 
(~0.7 mg) 
The tracer detected all 5 breast 
cancers, 
with 
visualization 
of 
axillary nodes where present. When 
comparison with Sestamibi, BN 
analogue showed higher T/B. [21] 
 
 
Table 3: Studies with in-human application of bombesin and its analogs in GIST and other 
types of cancer. 
Bombesin 
analogue 
Indication 
Dose 
Summary of Results 
[68Ga]-NeoBOMB1 
(antagonist) – AAA 
kit 
GIST 
150-250 MBq 
See protocol section 2.3.2 
[68Ga]-BZH3  
(agonist) 
Low 
Grade 
Gliomas 
na 
[68Ga]-bombesin and [18F]FDG-
PET 
predicted 
correctly 
malignant 
transformation 
or 
recurrence of the initial tumour 
(n=9). [22] 
[68Ga]-BZH3  
(agonist) 
GIST 
150-210 MBq 
(~ 3 nmol) 
Patients 
with 
GIST 
(n=17 
scheduled 
for 
therapy 
with 
imatinib because of unresectable 
primary or recurrent GIST or 
because of metastatic disease). 
Dynamic PET scans comparison 
with [18F]FDG.  
FDG discovered 25/30 lesions, 
BZH3 8/30. Once, the lesion was 
seen with BZH3 and not with 
FDG. [23] 
99mTc-[Leu13] BN  
(agonist) 
Colorectal cancer 
na 
13 (6 suspected colon cancer +7 
known to have rectal cancer). 
Cancer detected in 11/13 and 2 
false 
positives. 
5/5 
positive 
lymph nodes detected. Results 
confirmed 
by 
pathologic 
evaluation. [24] 
[68Ga]-NOTA-Aca-
BBN 
 
Healthy 
volunteers 
Glioma 
diagnosed 
by 
MRI 
111 ± 148 MBq 
Healthy volunteers (n=4): no 
adverse symptoms being noticed 
or reported. 
Patients with glioma (n=12): all 
MRI-identified lesions showed 
high signal intensity on 68Ga-

 
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NOTA-Aca-BBN PET/CT; the 
immunohistochemical 
staining 
confirmed a positive correlation 
between 
SUV 
and 
GRPR 
expression level. [25] 
 
2.3.2 [68Ga]-NeoBOMB1 in GRPR-positive malignancies 
 
The [68Ga]-NeoBOMB1 formulation, is currently under clinical investigation at the Innsbruck 
University, Austria. This is a Phase I/IIa study to evaluate safety, biodistribution, dosimetry and 
preliminary diagnostic performance of [68Ga]-NeoBOMB1 in patients with advanced TKI-
treated GIST using positron-emission tomography/computer tomography (PET/CT). 
An additional objective is to improve the diagnostic accuracy in GIST via PET/CT, including 
tumours with TKI-resistant subtypes. Better detection capability, classification and definition of 
lesion extent are expected from the use of [68Ga]-NeoBOMB1. 
Following completion of the phase-I part of the study (6 patients completed), the product was 
shown to present a favorable safety and tolerability profile, with no adverse events (AEs) 
related with the compound (interim report released in November 2017). Uptake in tumour was 
fast with good imaging performance already at 1h after administration (Figure 1), associated 
with rapid renal and blood clearance. 

 
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The locally compounded [68Ga]-NeoBOMB1 solution has been tested in the frame of a 
compassionate use program 
. Twenty-four patients were 
administered with [68Ga]-NeoBOMB1. No side effects have been reported and a good 
sensitivity was found compared to the conventional imaging. The results in four patients with 
prostate adenocarcinoma were reported by Nock et al. [7] . 
The formulation tested in 
 is similar to the formulation developed by AAA: the drug 
substance is exactly the same, it’s highly soluble and immediately bioavailable after 

 
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intravenous injection. It is also important to note that the final radiolabelled solution injected in 
patients is very similar for volume and pH in both cases, with the only exception of some 
excipients. The excipients used in the formulation developed by AAA (necessary to stabilize 
the product during lyophilisation, as well as to guarantee the long-term storage of the product) 
do not interact directly with the active substance and therefore do not have an impact on the 
disposition or clinical performance of the tracer. 
 
2.4 Rationale and risks/benefits  
 
The literature reports the GRPR overexpression in several malignant lesions but there is still a 
lack of precise data correlating GRPR overexpression to the molecular type of histological 
cancer as well as over the process of malignant transformation except for breast cancer [27]. 
In parallel, there are few studies focusing on GRPR imaging of primary tumours and metastatic 
lesions including lymph nodes. As there is a growing body of evidence suggesting that GRPR 
might be a valuable target for tumour identification and treatment, the Sponsor has conceived 
a study to investigate the diagnostic performance of NeoBOMB1, an antagonist with high 
affinity for GRPR, radioloabeled with a well-established PET isotope, Gallium-68 (68Ga).  
The Sponsor anticipates no biological effects of tracer dose (<50µg) of antagonist so no acute 
biological effects are expected. Regarding radioactivity, a dose of 3 MBq/kg ± 10% ranging 
within 150 to 250 MBq, is considered adequate to ensure appropriate imaging quality 
throughout the entire imaging protocol (latest time point at 4h p.i.) with 68Ga as radionuclide. 
This dose-range is in line with the recommended activity to obtain a good quality image for 
other DOTA-conjugated peptides)[26]. The phase I/IIa study currently ongoing at Innsbruck 
University is injecting patients using the dose described above. Data coming from Innsbruck 
(interim safety and imaging report) shows that the administration of 50μg [68Ga]-NeoBOMB1 
in six patients diagnosed with GIST demonstrated good tolerability in all patients. No SAE was 
observed, and few minor side effects (fatigue, headache, lecocyturia, anemia) was observed 
in 2 patients with pre-existing conditions, with low probability to be causually related to the 
study drug administration. Pharmakokinetic analysis revealed a high in vivo stability and rapid 
renal excretion of [68Ga]-NeoBOMB1 with highest accumulation in pancreas followed by kidney 
and liver. Overall these first clinical results shown both, a favourable safety profile and a 
preliminary good GRP-receptor targeting properties of [68Ga]-NeoBOMB1, when administered 
at the standard gallium-68 low-radiation imaging dose.  In terms of radioactive uptake kinetics, 
the interim report describes that following the administration of the compound there was a fast 
tumour-uptake, a rapid blood and renal clearance, which resulted in a good imaging 
performance as early as 60 minutes post-injection. In terms of dosimetry, the report describes 
a mean effective radiation dose of 0.026 mSv/MBq which is one-third lower than the calculated 
human-dose extrapolated from the animal model (0.039 mSv/MBq). With a maximum injected 
activity of 250 MBq the estimated effective dose would be 6.5 mSv per exam, which is lower 
that from the conventional [18F]FDG-PET imaging. 
The contribution of the low-dose CT is also to be contemplated. The amount of radiation dose 
from low-dose CT scan depends on different parameters, some related with the acquisition 
protocol (e.g. mA, mV), other intrinsic to the device used (e.g. single slice vs helical scanners). 
In the current protocol, to assess the pharmakcokinetic and the dosimetry of [68Ga]-

 
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NeoBOMB1, a maximum of 4 low-dose whole-body CT scans will be performed.  An overall 
whole-body dose of maximum 7 mSv (from 4 to 7 mSv) per CT scan is expected.  
For patients entering in the dosimetry group, a total theoretical radiation dose of 34,5 mSv is 
expected after administration of study drug plus the required four low-dose CT.. A total 
theoretical radiation dose of 20.5 mSv is expected for patients who will be included in the non-
dosimetry group except for patients with PC who will receive an expected radiation dose of 
27.5 mSv due to the additional CT scan required for them. In all the cases, the estimated 
effective dose will fall in the risk category level III as per the report 103 of the International 
Commission on Radiological Protection (ICRP) and are justified by a level of benefit as 
“Acquisition of knowledge, directly aimed at prevention or cure of serious disease”. The 
standard radiation-exposure minimization measures including frequent bladder voiding is 
always a standard recommendation practice with radioligands presenting renal clearance, and 
is required in the current protocol. It is noteworthy reminding that this estimated total radiation 
dose is well aligned with the FDA recommendation of 30 mSv for adult research subjects 
receiving a single dose (Guidance for Industry and Researchers; “The Radioactive Drug 
Research Committee: Human Research without an Investigational New Drug Application”, 
August 2010). 
 
Another expected benefit of [68Ga]-NeoBOMB1-PET relies on the potential early diagnostic 
detection of a recurrence, whether local relapse or distant metastasis, among those patients 
diagnosed with tumours expressing GRPR. Early and accurate detection translates in 
improved planning of treatment with classical therapeutic options, i.e. locoregional ablation 
techniques. Moreover, if [68Ga]-NeoBOMB1 targets cancerous lesions with sufficient specificity 
and sensitivity, new treatment possibilities including peptide receptor radionuclide therapy may 
emerge.  
In light of the disease status of the patients eligible for our study and the low risk of 
administration of [68Ga]-NeoBOMB1, the benefit-risk balance is favourable and weights for 
patient’s benefit.   
 
3 Study design 
 
3.1 Description of the study 
 
Rationale of the design: 
This is a Phase II, multi-center, open label, single dose study in cancer patients with tumour 
types known to overexpress GRPR, including breast, prostate, colorectal, small-cell and non-
small cell lung. 
The main objective of the Phase II study is the characterization of the preliminary targeting 
properties of [68Ga]-NeoBOMB1 in patients with malignancies known to overexpress GRPR to 
assess the tumour-background ratio. The secondary objectives of the clinical trial are safety 
and tolerability and dosimetry aspects. All the objectives, with the exception of the secondary 
one relative to biodistribution and dosimetry that will be assessed within the dosimetry group, 
will be assessed in the overall population (n=50). Analyses of the dosimetry group data will 

 
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lead to the optimal time window for PET/CT imaging for future clinical trials.  However, in the 
case that the Sponsor obtains the results of the dosimetry and biodistribution assessments 
from at least 3 patients of the dosimetry group before the full completion of the study 
recruitment and the results show that the optimal time window is different from 1h30±30min or 
2h30±30min as initially predicted by the Sponsor, the timepoints of the whole-body PET/CT 
scans for the remaining patients included in the non-dosimetry group will be adjusted. 
 
Study conduct: 
Population will be divided in two groups: 
• 
Phase-II dosimetry group: 10 patients bearing breast and prostate cancer will undergo 
additional assessments to confirm previous data on tracer bio-distribution, radiation 
dosimetry, residence time for critical organs, and absorbed dose critical organs for 
[68Ga]-NeoBOMB1. Serial venous whole blood and urine samples will be collected for 
pharmacokinetic characterization. Patients will undergo a 15-min-static whole-body PET 
images at 15 min p.i.at 1h±15 min, 2h±15 min and 4h±30 min to determine absorbed 
doses to normal organs and to target tumour lesions. Venous whole blood samples will 
be collected at pre-dose (0), 5, 10, 20, 30±5, 60±5 min, and at 2h±10 min and 3-4 h±10 
min p.i. Urine samples from 0-2 h and from 2-4 h p.i. will also be collected. 
• 
Phase-II non-dosimetry group: 40 patients will be enrolled in the second group. PET-
imaging will be reduced to 2 whole body scans at 1h30±30min and at 2h30±30min likely 
to be a 15-min static late PET for all tumour-types. Only prostate tumour patients will 
undergo an additional early 5-min static PET scan to better assess lymph node 
metastases (if applicable). Blood and urine sampling will be omitted. 
 
Figure 2: Overall study flow chart for dosimetry group 

 
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Figure 2bis: Overall study flow chart for non-dosimetry group 
 
3.2 Study objectives 
 
3.2.1 Primary Study Objective 
 
• 
To characterize preliminary targeting properties of [68Ga]-NeoBOMB1 in patients with 
malignancies known to overexpress GRPR. 
 
3.2.2 Secondary Study Objectives 
 
• 
To assess safety and tolerability of a single diagnostic dose of [68Ga]-NeoBOMB1 
administered as an intravenous bolus injection. 
• 
To assess the bio-distribution, pharmacokinetics, radiation dosimetry, and absorbed 
dose critical organs for [68Ga]-NeoBOMB1 in a limited number of patients. 
• 
To establish the optimal threshold, expressed as Standardized Uptake Value (SUV), to 
discriminate PET imaging positive results from negative ones. 
• 
To estimate the [68Ga]-NeoBOMB1 PET lesion-based and patient-based imaging 
performance relative to a comparable standard imaging. 
• 
To estimate [68Ga]-NeoBOMB1 PET lesion-based and patient-based diagnostic 
performance relative to cytology and/or histopathology findings (e.g. IHC). 
 
 
 

 
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3.3 Study Endpoints 
 
3.3.1 Primary Study Endpoint 
 
• 
Number and location of tumour lesions detected by [68Ga]-NeoBOMB1 overall and for 
each tumour type 
• 
Calculation of the ratio tumour/background SUV and calculation of percentage 
absorbed dose in tumour overall and for each tumour type. 
 
3.3.2 Secondary Study Endpoints 
 
• Standard safety parameters (clinical monitoring, laboratory, ECG) 
• Tolerability and safety of the administration of a diagnostic dose of [68Ga]-NeoBOMB1 
in patients with malignancies known to overexpress GRPR as determined by absence 
of: 
- increased number of SAEs compared to other peptide-based radiotracers;  
- clinically relevant changes of physiological parameters (blood pressure, heart 
rate, ECG findings) 
• Generation of decay corrected tissue TACs from [68Ga]-NeoBOMB1 PET/CT images 
in normal organs, tumour lesions.  
• Quantification of urinary excretion of [68Ga]-NeoBOMB1 
• Calculation of half-life of [68Ga]-NeoBOMB1 in blood 
• Generation of non-decay-corrected TACs from [68Ga]-NeoBOMB1 PET/CT images in 
normal organs, tumour lesions 
• Calculation of residence times in organs and tumour lesions of [68Ga]-NeoBOMB1 
• Calculation of absorbed doses and effective whole body dose of [68Ga]-NeoBOMB1 
• Calculation of the SUV of each lesion 
• Number and location of tumour lesion detected by [68Ga]-NeoBOMB1 in comparison 
with comparable standard imaging modalities such as FDG-PET 

 
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• Calculation of the [68Ga]-NeoBOMB1 PET overall, positive and negative agreement on 
a lesion-by-lesion basis as well as on a patient basis relative to the standard imaging 
overall and for each tumour type  
• Comparison of number of patients with tumour lesions detected and number of 
tumour lesions detected by [68Ga]-NeoBOMB1 with cytology and/or histopathology 
from archival and/or recent biopsy specimens 
• Calculation of the [68Ga]-NeoBOMB1 PET sensitivity and specificity on a lesion-by-
lesion basis for all lesions with associated biopsy data, and on a patient basis relative 
to histopathology / cytology data 
 
 
 
3.4 Study population / Selection of subjects 
 
3.4.1 Inclusion criteria 
 
1. Subjects must be at least 18 years of age 
2. Subjects must have signed and dated an informed consent prior to any study-specific 
procedures. 
3. Subjects with histologically-confirmed tumour, for whom a recent biopsy (not older than 
6-month-old) has been performed. 
4. Dosimetry group: 
• 
Luminal breast cancer 
• 
Adenocarcinoma of the prostate 
5. Non-dosimetry group: 
• 
Luminal breast cancer 
• 
Adenocarcinoma of the prostate 
• 
Small cell lung cancer 
• 
Non-small cell lung cancer 
• 
Colorectal carcinoma 
6. At least one malignant lesion detected via functional or morphological imaging (PET 
combined to appropriate tracer according to tumour type (PET combined to appropriate 
tracer according to tumour type, CT, MRI) within 3 months prior to [68Ga]-NeoBOMB1 
administration. 
7. The Eastern Cooperative Oncology (ECOG) performance status 0-2. 
8. Subjects must agree to use highly effective methods of contraception (female partners 
of male participants should use highly effective methods of contraception) during the 
trial. 
 

 
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3.4.2 Exclusion criteria  
 
1. Renal insufficiency or an eGFR <50 ml/min/1.73m2.  
2. Haematological toxicity grade > 2 (Toxicity Grading Scale in vaccine clinical trials) 
3. Participation in any other investigational trial within 30 days of study entry. 
4. Subjects with positive pregnancy test (Urine dipstick), and/or currently breast-feeding  
5. Concurrent severe illness or clinically relevant trauma within 2 weeks before the 
administration of the investigational product that might preclude study completion or 
interfere with study results. 
6. Concurrent bladder outflow obstruction or unmanageable urinary incontinence. 
7. Known or expected hypersensitivity to [68Ga]-NeoBOMB1, or any excipient present in 
[68Ga]-NeoBOMB1. 
8. Any condition that precludes raised arms position 
9. Prior administration of a radiopharmaceutical within a period corresponding to 8 half-
lives of the radionuclide. 
10. History of somatic or psychiatric disease/condition that may interfere with the objectives 
and assessments of the study. 
 
3.4.3 Patients recruitment  
 
Recruitment of subjects is center competitive, i.e. there is no maximum recruitment per center, 
rather all centers will stop recruiting when the 50th subject is undergoing [68Ga]-NeoBOMB1-
PET.  
To accurately answer the primary objective, recruitment of subjects requires that each of the 
5 tumour types be equally represented. Therefore, 5 subgroups accounting with 10 subjects 
bearing the same tumour type will be formed. 
The dosimetry group will be formed by 5 patients with breast cancer and 5 patients prostate 
cancer. Patients will decide by themselves whether they want to participate in the dosimetry or 
the non-dosimetry group. 

 
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Figure 3: Patients’ recruitment chart 
 
3.4.4 Patient ID definition 
 
A unique subject identification number will be assigned at the start of the screening period to 
each subject who signs the informed consent form. This number will identify the subject 
throughout the study and ensure the identity confidentiality of the subject. 
 
Subject identification numbers will include a 2-letter country code, a 2-digit site code and a 3-
digit subject number (ex: 
 for the first recruited patient at site 
 in France). 
Kits will be allocated for single subject use. 
 
3.4.5 Withdrawal of trial subjects after trial start 
 
Reasons for removal investigational treatment or observation might include: 
• 
Withdrawal of consent 
• 
Pregnancy 
• 
Significant protocol deviation 
• 
Subject non-compliance 
• 
Adverse event 
• 
Other safety concern of the investigator or sponsor 
• 
Death 
• 
Lost to follow-up 
 

 
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Subjects have the right to withdraw from the study at any time and for any reason without 
prejudice to their future medical care by the physician or at the institution. 
Withdrawal of consent for the study means that the subject does not wish to receive further 
investigational treatment and does not wish or is unable to continue further study participation. 
Subject data up to withdrawal of consent will be included in the subject’s study data, but no 
further information will be collected. 
For any patient who has received Investigational Medicinal Product (IMP) and withdrew 
prematurely from the study every effort should be made for attendance of a safety follow-up 
visit. The primary reason for withdrawal from the study should be documented. Patients will 
not be followed for any reason after consent has been withdrawn. 
The investigator has the right to discontinue a patient from IMP or withdraw a patient from the 
study at any time. The primary reason for withdrawal from the study should be documented.  
If a patient discontinues the study participation after administration of [68Ga]-NeoBOMB1 and 
generation of all measurements for reasons unrelated to an adverse event and does not object 
to the use of the generated data, the data will be used. If a patient discontinues the study 
participation before administration of [68Ga]-NeoBOMB1, the patient will be replaced by 
another patient. However, if the withdrawal is after the administration, the patient will not be 
replaced. 
 
3.4.6 Closure of trial sites/Premature termination of the clinical trial 
 
3.4.6.1 Premature termination of trial 
 
The sponsor has the right to terminate the trial prematurely at any time. 
This might be if there are any relevant medical or ethical concerns, or if completing the trial is 
no longer practicable. If such action is taken, the reasons for terminating the trial must be 
documented in detail. All trial subjects still under treatment at the time of termination must 
undergo a final examination, which must be documented.  
Premature termination of the trial will be considered if: 
• 
The risk-benefit balance for the trial subject changes markedly 
• 
It is no longer ethical to continue application of [68Ga]-NeoBOMB1 
• 
The sponsor considers that the trial must be discontinued for safety reasons  
• 
It is no longer practicable to complete the trial 
 
The sponsor decides on whether to discontinue the trial in consultation with the PI. 
In case of discontinuation of the trial, the EC and Competent Authority (CA) must be informed 
within 15 days of early termination. 
4 Study procedures and schedule of assessments 
 
4.1 Study procedures 
 

 
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4.1.1 Informed consent form 
 
It is the responsibility of the PI, or a person delegated by the PI to obtain written informed 
consent from each subject prior to participation in the trial, following adequate explanation of 
the aims, methods, anticipated benefits and potential hazards of the study.  
The PI or designee will explain the patients are under no obligation to enter the trial and that 
they can withdraw at any time during the trial, without having to give a reason. 
No clinical trial procedures will be conducted prior to taking consent from the participant. 
Consent will not denote enrollment into the trial.  
A copy of the signed Informed Consent Form (ICF) will be given to the participant. The original 
signed and dated form will be retained at the study site. 
If new safety information results in significant changes in the risk/benefit assessment, the 
consent form will be reviewed and updated if necessary and subjects will be re-consented as 
appropriate. 
 
4.1.2 Physical examinations 
 
Physical examinations will be performed at all visits except at Day 2 for patients included in 
the non-dosimetry group. All of them will be performed by trained medical personnel only, prior 
to IMP administration on the dosing day. Any abnormal findings will be recorded as AEs. 
Furthermore, auscultation of lungs and heart and palpation of abdomen will be performed 
 
4.1.3 Vital signs 
 
Vital signs will be measured at all visits except at Day 2 for patients included in the non-
dosimetry group.  
On injection/PET day, i.e. Day 1, vital signs will be recorded  
• 
at pre-dose, immediately after radiotracer injection, 30 min p.i. and after the last image 
acquisition (about 4h) among patients of the dosimetry group. 
• 
at pre-dose, 30 min p.i. among patients of the non-dosimetry group. 
Heart rate and blood pressure will be measured after patient has been in a seating position for 
5 minutes. 
 
4.1.4 ECG 
 
A standard 12-lead ECG assessment will be performed at all visits except at Day 2 for patients 
included in the non-dosimetry group. The following parameters must be recorded: RR, PR, 
QRS, and a more extended QT-time (QTc) evaluation according to ICH E14, and heart rate. 
On injection/PET day, i.e. Day 1, ECG will be recorded  

 
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• 
at pre-dose, immediately after radiotracer injection, 30 min p.i. and after the last image 
acquisition (about 4h) among patients of the dosimetry group. 
• 
at pre-dose, and 30 min p.i. among patients of the non-dosimetry group. 
ECGs for each patient will be obtained from the same machine whenever possible. To 
minimize variability, it is important that patients be in a rest position for > 5 minutes prior to 
ECG evaluation. Body position should be consistently maintained for each ECG evaluation to 
prevent changes in heart rate. Environmental distractions (e.g., television, radio, conversation) 
should be avoided during the pre-ECG resting period and during ECG recording. ECGs should 
be performed prior to any scheduled vital signs measurements and blood draws. 
For safety monitoring purposes, the investigator or designee must review, sign, and date all 
ECG tracings. 
 
4.1.5 Routine laboratory exams and pregnancy test 
 
Routine laboratory exams will be performed at all visits except at Day 2 for patients included 
in the non-dosimetry group. 
Clinical Laboratory: 
Blood chemistry: Non-fasting glucose, Urea, Creatinin, eGFR (calculated), Bilirubin, Na, K, 
Cl, Ca, GOT (ASAT), GPT (ALAT), γGT, ALP, pancreatic amylase, pancreatic lipase, LDH, 
CK, CRP, albumin 
Haematology: Haemoglobin, haematocrit, RBC count, absolute WBC count (neutrophils, 
eosinophils, basophils, lymphocytes, monocytes), platelets 
Coagulation parameters: Quick, INR, aPTT, fibrinogen 
Pregnancy test (in women of childbearing potential): dip-stick 
Urinalysis via dip-stick: appearance, colour, pH, protein, glucose, blood 
 
The total volume of blood required per patient for standard clinical laboratory assessments will 
be approximately 16.5 mL for 3 full tubes on each sampling occasion. 
Among patients of the dosimetry group, routine laboratory exams will be performed at 
Screening, Day 1, Day 2, Day 7±1 and Day 14±2. In addition, 1 mL of venous whole blood per 
time-point will be drawn for the biodistribution assessment at Day 1. A total volume of 90.5 mL 
venous blood will be withdrawn.  
Among patients of the non-dosimetry group, routine laboratory exams will be performed at 
Screening, Day 1, Day 7±1 and Day 14±2 for a total volume of withdrawn venous blood of 66 
mL.  
 
4.1.6 Imaging  
 
[68Ga]-NeoBOMB1 imaging will be performed using a standard integrated PET/CT system. All 
imaging will be performed at the Department of Nuclear Medicine.  

 
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It is important to remember to record the patients’ weight and height in the PET system 
software.  
The patient must be hydrated per os with at least 750 mL of bottled drinking water 1 h before 
of image acquisition.  
A standard PET/CT tomograph consists of a LSO PET system combined with a multi-row spiral 
CT system. 
Immediately before the PET/CT examination, patients are requested to empty their bladder. 
Patients are positioned supine with raised arms and head-first on the common patient handling 
system in accordance with standard CT practice.  
First, a topogram will be acquired over 1,024 mm axially. Coaxial whole-body imaging ranges 
will be defined on the topogram, covering an area from the skull to the mid-thighs (6-7 PET 
bed positions, or 90–110 cm, depending on the size of the patient). CT shall be performed for 
attenuation correction purposes and anatomical reference for subsequent PET acquisition. 
During the CT acquisition a limited breath hold protocol will be followed, which required the 
patients to hold their breath in normal expiration. After completion of the CT, patient’s bed 
moves automatically to the PET gantry, where 3D PET emission scanning subsequently will 
starts in the caudocranial direction.  
 
The administration of the radiotracer will be performed using a venous access, injection volume 
will be up to 5.5 ml with a slow bolus paradigm however conserving the same procedure time 
for all the patients. During this slow bolus, vital signs will be monitored. The radiolabeling 
protocol ensures that standard conditions are kept in terms of peptide mass. 
In case of SAEs, the injection will be stopped immediately and reported based on the Toxicity 
Grading Scale in vaccine clinical trials. 
 
Patients of the dosimetry group will undergo 4 sequential PET/CT scans. The IMP [68Ga]-
NeoBOMB1 injection should occur prior to the start of any imaging. Patients should be 
positioned and imaging should begin at 15min, 1h±15min, 2h±15min and 4h±30min post IMP 
injection with PET/CT scans consisting of low dose attenuation correction CT scans followed 
by PET images acquired from the head through the mid-thigh (approximately 6-7 beds 

 
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depending on patient height). PET data will be corrected for photon attenuation, dead-time, 
random events and scatter.   
 
Figure 4: Dosimetry group PET imaging flow chart 
1WB PET/CT : low-dose for 4 WB PET/CT from the vertex to the upper thighs for attenuation correction followed by a 
total-body PET examination  
Affinity parameters of the [68Ga]-NeoBOMB1 (KD) will be used to create a model able to predict 
dose to tumour and relevant organs (pancreas, kidney, liver) expected to present the greatest 
relative tracer uptake when a bombesin antagonist (such as [68Ga]-NeoBOMB1) is 
administered.  
The images will be analysed with regards to the diagnostic suitability of [68Ga]-NeoBOMB1 for 
tumour targeting as well as the safety of the procedure (whole body dosimetry of [68Ga]-
NeoBOMB1).  
 
Patients of the non-dosimetry group will undergo 2 whole-body PET/CT scans at 90±30min 
and at 150±30 min. Patients with prostate cancer will also undergo a 5-min static PET/CT scan 
on relevant regions for lymph node imaging purpose (if applicable).  

 
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Figure 5: Non-dosimetry group PET imaging flow chart 
1WB PET/CT: low-dose from the vertex to the upper thighs for attenuation correction followed by a total-body PET examination  
Data Reconstruction and Image Analysis  
The CT transmission images are used for attenuation correction of the PET emission data. 
After scatter and attenuation correction, PET emission data must be reconstructed using an 
attenuation-weighted ordered-subsets maximization expectation approach with 2 iterations 
and 8 subsets on 128x128 matrices and with a 5-mm Gaussian post-reconstruction filtering.  
Semi-quantitative analysis (SUVmax and mean) per tumour type group and time point will be 
conducted to establish pathological thresholds or pathological/physiological ratio thresholds 
and determine [68Ga]-NeoBOMB1-PET diagnostic performance. 
Similarly, organs receiving the highest organ dose (HT) will be identified and radiation doses 
per organ (μGy/MBq) as well as effective organ doses (μSv/MBq) will be computed. 
 
PET data will be transferred to the central imaging center in an anonymized way to protect 
patient’s privacy. A procedure is detailed in a separate central imaging reading center manual 
provided to each site. Briefly, for data transfer, 4 types of files are generally used: Excel info 

 
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file, Excel biokinetic PET/CT data, PET/CT DICOM files and additional files (containing the 
data of the other tests). 
The Excel info file shall include all procedures performed in every patient and relative 
demographic (age, weight, height, etc.)  as well as the Patient’s ID.  
The Excel biokinetics file shall include all PET/CT non-imaging data (activity data) for the 
different time points (according to the PET/CT protocol) for every measured organ as well as 
the measured volumes for each organ in every patient. This information will be transferred as 
an MS Excel file (for processing) and as printed documents signed by the person in charge 
(for verification and control).  
The DICOM files will contain the anonymized raw PET/CT data (using the internal Patient IDs) 
plus RT structure DICOM files for the structures drawn for the organs at risk (ROIs).  
The additional files consist of the additional tests performed on the patients such as 
hemograms, semi-quantitative urine analyses and organ volume measurements. This 
information is to be also anonymized and renamed with the assigned internal Patient IDs. This 
information will be sent in digital form as well as printed documents (for verification and control). 
All the electronic information (DICOM files, MS Excel files and PDF files) will be stored on 
DVDs (original and backup copy in case of having any trouble with the original one).   
 
All other relevant info relative to patients must be sent to the central reading center, including 
the standard morphologic imaging study that has detected the malignancy or its recurrence, 
likely to be CT, MRI or PET, in DICOM format, with the same anonymization method used for 
the internal Patient IDs. An excel file will include specific info about such study, the date of 
acquisition, the protocol used, the injected tracer if pertinent, the scan duration, the 
reconstruction algorithm as well as the medical interpretation from the radiologist/nuclear 
medicine physician.  
 
 
4.1.7 Biodistribution and dosimetry  
 
Sequential venous blood samples of 1 mL at baseline (immediately prior to injection, time 0) 
and at 5, 10, 20, 30±5, 1h±5min, 2h±10min and 3-4h±10min as well as 1ml-urine samples from 
the one produced over 0-2h and 2-4h after the end of infusion for dosimetric measurements 
will be collected. 
Dosimetry calculations will be issued from the analyses of organs receiving the highest dose, 
identified visually. ROIs/VOIs will be placed over these organs to determine relative radiotracer 
uptake calculated as a percentage of the injected dose per gram of tissue (%ID/g). Tissue 
activity curves will be generated from the amount of radioactivity in one given tissue at a given 
moment over the amount of radioactivity present in the blood at that given moment and integrals 
will be calculated accordingly through dynamic acquisitions. Time activity curves ([TAC] - (u(t) 
in % injected dose per gram of tissue), describing %ID/ROI of the activity amount injected vs. 
time will be derived, considering renal excretion activity.  
Tissue ACs will be fitted to mono- and bi-exponential curves to yield cumulative activities. Urine 
samples from 0-2h and from 2-4h post-injection will be collected to complete dosimetry and 
biodistribution assessments. The absorbed dose (μGy/MBq) will be transformed into formal 

 
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biological equivalent dose for radiation exposure (μSv/MBq) to finally yield an effective 
radiation dose, a factor between others that could help providing an estimation of total danger 
to the whole organism. 
 
4.1.8 Assessment of GRPR expression  
 
Assessment of GRPR expression must be assessed while the study is ongoing within 4 weeks 
after IMP injection. GRPR expression is analyzed by a single central laboratory to ensure 
homogeneity of procedures. The technique used by the central laboratory together with the 
requirements of preparation of the tissue samples is detailed in a separate laboratory manual 
provided to each study site. Briefly, a surgery/biopsy specimen of the malignant lesion sampled 
6 months prior to IMP injection at the earliest will be assessed by immunohistochemical 
staining. 
 
4.1.9 Adverse Events and Concomitant Medications 
 
Adverse events and concomitant medications will be reported and recorded from the signature 
of the (ICF) until the end of the study (Section 6 of the protocol).  
 
4.2 Schedule of assessments 
 
4.2.1 Screening period (Visit 0, days –28 to – 1) 
 
The screening examinations must be performed between 1 and 28 days before being enrolled 
in the study (i.e. administration of [68Ga]-NeoBOMB1). Only subjects fulfilling all the inclusion 
and none of the exclusion criteria will be accepted in the study. 
The following study screening assessments are to be completed within 1 to 28 days prior to 
study entry: 
• 
Signed and dated informed consent 
• 
Reviewed inclusion and exclusion criteria 
• 
Demographic data: age and sex 
• 
Medical history: relevant prior or persisting illnesses including known allergies, prior 
anaphylactic reactions, metabolic disorders, vascular disorders, hypertension, history 
of stroke or myocardial infarction, other known malignancies, prior treatment 
• 
Concomitant medication 
• 
Physical examination: weight, auscultation of lungs and heart, oral inspection, 
abdominal palpation 
• 
Vital signs: blood pressure, heart rate  
• 
Routine ECG including frequency-corrected QT-time 
• 
Haematology, Blood chemistry, Coagulation parameters, Urinalysis 
• 
Urine dipstick pregnancy test (in women of childbearing potential) 

 
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4.2.2 Injection/PET Imaging day (Day 1/Visit 1) 
 
Before administration 
Hospitalization will occur on the day of administration of [68Ga]-NeoBOMB1. 
For all patients, the following study assessments will be performed on the day of administration 
of [68Ga]-NeoBOMB1: 
• 
Participant will be asked to drink 750 ml of water within 1h before image acquisitions 
• 
Control of dated informed consent 
• 
Review of inclusion and exclusion criteria 
• 
Control of adverse events and concomitant medications 
• 
Physical examination: weight, auscultation of lungs and heart, oral inspection, 
abdominal palpation 
• 
Vital signs: blood pressure, heart rate 
• 
12-lead ECG including frequency-corrected QT-time 
• 
Haematology, Blood chemistry, Coagulation parameters: Quick, INR, aPTT, 
fibrinogen, Urinalysis 
• 
Urine dipstick pregnancy test (in women of childbearing potential)  
• 
Venous blood sampling (~1 ml) for radioactivity assay (only for dosimetry group) 
• 
Urine collection for radioactivity assay (only for dosimetry group) 
• 
Histopathologic evaluation 
• 
Concomitant medications can be administered from 4h after the [68Ga]-NeoBOMB1 
administration. 
 
 
During and after administration 
 
For patients included in the dosimetry group, the following safety assessments will take place: 
• 
Vital signs: blood pressure, heart rate immediately after administration of [68Ga]-
NeoBOMB1, at 30 min after administration and after the last whole-body scan (around 
4 h) 
• 
Routine ECG including frequency-corrected QT-time immediately after administration 
of [68Ga]-NeoBOMB1, at 30 min after administration and after the last whole body scan 
(around 4 h)  
• 
Venous whole blood sampling (~1 ml) for radioactivity assay at 5, 10, 20, 30±5min, 
60±5 min and 2h±10 min and 3-4h±10 min.  
• 
Urine collection for radioactivity assay (~1 ml) from 0-2h and from 2-4h. In addition, the 
subjects will be requested to void immediately. 
• 
Static whole-body PET at 15min, 1h±15 min, at 2h±15 min and at 4h±30 min. 
 
For patients of the non-dosimetry group, the following safety assessments will take place: 
• 
Vital signs: blood pressure, heart rate 30 min p.i. 
• 
Routine ECG including frequency-corrected QT-time 30 min p.i.  
• 
Static PET scan between 0 and 5 min only for the prostate subgroup (if applicable) 

 
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• 
Static whole-body PET at 1h30±30 min and at 2h30±30 min 
 
 
4.3 Safety follow-up visits (Day 2/Visit 2, Day 7/Visit 3 and Day 14/Visit 4) 
 
Patients will be discharged on the day 1 after administration of [68Ga]-NeoBOMB1 in case of 
no or minor adverse events that do not contradict such a discharge. 
FU visits are scheduled 1 day (Visit 2), 7±1 days (Visit 3) and 14±2 days (Visit 4) after 
administration of [68Ga]-NeoBOMB1 and will encompass:  
- 
Physical exam, 
- 
Vital signs, 
- 
12-lead ECG 
- 
Blood sampling to determine haematological and biochemical parameters, 
- 
Dipstick test for urinalysis 
- 
Check-up of concomitant medication, 
- 
Assessment for adverse events. 
 
On Day 2, patients included in the non-dosimetry group will receive a FU phone call to assess 
any potential adverse events, allergic reactions and concomitant treatments. For this group of 
patients, Day 7±1 is an optional FU physical visit and can be replaced by a phone call to assess 
any potential adverse events, allergic reactions and concomitant treatments. 
 
4.4  Optional routine clinical disease follow-up 
 
If available, within 3 months from IMP injection, data generated from the routine clinical follow-
up of the patients in the frame of routine patients’ management will be collected to help with 
the interpretation of previous focal uptake of [68Ga]-NeoBOMB1 PET which was not 
corresponded to detectable morphological lesions on CT/MRI 
 
4.5 Visit and Assessment Schedule  
 
Phase II dosimetry group:

 
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1. 
Standard conventional imaging required  
2. 
Urine dipstick test 
3. 
Negative urine pregnancy test at Baseline and within 24 hours prior to administration.  
4. 
Time-points: pre-injection, 5, 10, 20, 30±5, and 1h±5min, 2h±10min, 3-4h±10min post-injection 
5. 
Time-points: pre-injection, from 0-2h and from 2-4h post-injection 
6. 
WB PET/CT: low-dose CT, non-enhanced CT from the vertex to the upper thighs for attenuation correction followed by a total-body PET examination  
Time point 
 
Visit 0 
Screening 
Visit 1 
PET Imaging Day 
Visit 2  
FU 
 
Visit 3 
FU 
 
Visit 4 
FU 
Optional 
routine 
clinical 
disease 
FU7 
Examination/Evaluation 
Day 
 -28 to -1 
1 
2 
7±1 
14 ±2 
Max 90 
HH:mm 
  
Pre-
dose 
0-5 min 
5-15 
min 
20 min 
30 min 
1h 
2h 
3-4h 
  
 
 
 
Informed Consent 
● 
  
  
  
 
 
  
  
 
  
 
 
 
Inclusion / Exclusion criteria1 
● 
 
  
  
 
 
  
  
 
  
 
 
 
General 
  
  
  
  
 
 
  
  
 
  
 
 
 
Demographic Data 
● 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
● 
● 
  
  
 
 
  
  
 
 
 
 
 
Physical Exam 
● 
● 
  
  
 
 
  
  
 
● 
● 
● 
 
Vital Signs 
● 
● 
●  
 
 
● 
 
 
● 
● 
● 
● 
 
Blood analysis (hemato, biochemistry, 
coagulation) 
● 
● 
  
  
 
 
  
  
 
● 
● 
● 
 
Urine analysis2 
● 
● 
  
  
 
 
  
  
 
 ● 
● 
● 
 
Pregnancy Test3 
● 
● 
  
  
 
 
  
  
 
  
 
 
 
12-lead ECG 
● 
● 
 ● 
 
 
 ●  
  
 
● 
● 
● 
● 
 
Concomitant Medications 
● 
● 
  
  
 
 
  
  
 
● 
● 
● 
● 
Baseline findings / Adverse Events 
● 
● 
● 
● 
● 
● 
IMP Administration & Dosimetry 
  
  
  
  
 
 
  
  
 
  
 
 
 
[68Ga]-NeoBOMB1 Injection 
  
  
● 
  
 
 
  
  
 
  
 
 
 
Blood sampling / radioactivity4 
  
● 
● 
 ● 
● 
● 
●  
 ● 
● 
  
 
 
 
Urine collection / radioactivity5 
  
 ● 
● 
  
 
 
 
[68Ga]-NeoBOMB1 PET/CT imaging 
  
  
  
  
 
 
  
  
 
  
 
 
 
Static, whole Body6 
  
  
  
●  
 
 
● 
● 
● 
  
 
 
 
GRPR expression assessment8 
●  

 
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7. 
Any relevant data generated from the routine clinical disease follow-up will be collected: CT/MRI, biopsy, physical examination 
8. 
GRPR expression assessment must be performed within 4 weeks after IMP injection 
 
Phase II non-dosimetry group: 
Time point 
 
Visit 0 
Screening 
 
Visit 1 
PET Imaging Day 
Visit 2 
FU4 
 
Visit 3 
FU5 
 
 
Visit 4 
FU 
 
Optional 
routine 
clinical 
disease 
FU7 
Examination/Evaluation 
Day 
-28 to -1 
 
1 
2 
7±1 
14±2 
Max 90 
HH:MM 
 
Pre-dose 
0-5 min 
30 min 
1h30±30min 
2h30 ± 
30 min 
 
 
 
 
Informed Consent 
● 
 
 
 
 
 
 
 
 
 
Inclusion / Exclusion criteria1 
● 
 
 
 
 
 
 
 
 
 
General 
 
 
 
 
 
 
 
 
 
 
Demographic Data 
● 
 
 
 
 
 
 
 
 
 
Medical History 
● 
● 
 
 
 
 
 
 
 
 
Physical Exam 
● 
● 
 
 
 
 
 
● 
● 
 
Vital Signs 
● 
● 
● 
● 
 
 
 
● 
● 
 
Blood analysis (hemato, biochemistry, 
coagulation) 
● 
● 
 
 
 
 
 
● 
● 
 
Urine analysis2 
● 
● 
 
 
 
 
 
● 
● 
 
Pregnancy Test3 
● 
● 
 
 
 
 
 
 
 
 
12-lead ECG 
● 
● 
● 
● 
 
 
 
● 
● 
 
Concomitant Medications 
● 
● 
 
 
 
 
● 
● 
● 
● 
Baseline findings / Adverse Events 
● 
 
● 
 
● 
● 
● 
● 
IMP Administration 
 
 
 
 
 
 
 
 
 
 
 
[68Ga]-NeoBOMB1 Injection 
 
 
 
● 
 
 
 
 
 
 
 
[68Ga]-NeoBOMB1 PET/CT imaging 
 
 
 
 
 
 
 
 
 
 
Static scan (prostate cancer –if applicable) 
 
 
● 
 
 
 
 
 
 
 
Static, whole-body6 
 
 
 
 
● 
● 
 
 
 
 
GRPR expression assessment8 
 
● 
1. 
Standard conventional imaging required  
2. 
Urine dipstick test 
3. 
Negative urine pregnancy test at Baseline and within 24 hours prior to administration. 
4. 
Phone call  

 
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5. 
Visit or phone call 
6. 
WB PET/CT: low-dose for 4 WB PET/CT from the vertex to the upper thighs for attenuation correction followed by a total-body PET examination  
7. 
Any relevant data generated from the routine clinical disease follow-up will be collected: CT/MRI, biopsy, physical examination 
8. 
GRPR expression assessment must be performed within 4 weeks after IMP injection 
 
 

 
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5 Study medication 
 
5.1 Name and description of Investigational Medicinal Product 
 
The name and pharmaceutical form of the IMP is [68Ga]-NeoBOMB1 kit for 
radiopharmaceutical preparation. 
The IMP is a sterile 2-vial kit which consists of: 
• 
Vial 1: NeoBOMB1, 50 µg, powder for solution for injection, to be reconstituted with a 
solution of gallium-68 chloride (68GaCl3) in HCl eluted from a 68Ge/68Ga generator; 
• 
Vial 2: Reaction buffer. Vial 2 is to be added to the reconstituted Vial 1. 
 
The kit has to be used in combination with a solution of 68Ga in HCl provided by a 68Ge/68Ga 
generator to obtain 68Ga-NeoBOMB1 solution for injection, being the Radiolabelled Imaging 
Product, which can be directly injected to the patient.  
The volume of 68Ga-NeoBOMB1 solution for injection, corresponding to the radioactive dose 
to be administered, is calculated according to the estimated time of injection, on the basis of 
the current activity provided by the generator and of physical decay of the radionuclide (half-
life = 68 min). 
It is a mono-dose product. 
Vial 1 is a powder for solution for injection containing 50 µg NeoBOMB1 as active ingredient. 
The powder is packed in 10 mL Ultra inert Type I Plus glass vials.  
Vial 2 Reaction buffer contains no active ingredient. 
Reaction buffer solution is contained in a 10 mL cyclic olefin polymer vial. 
 
The kit will be prepared, packaged and released according to Sponsor Standard Operating 
Procedures (SOPs), Good Manufacturing Practice (GMP) guidelines, ICH GCP guidelines, and 
applicable local laws/regulations. 
 
 
 
5.2  IMP administration 
 
[68Ga]-NeoBOMB1 must be prepared and administered at the investigational site by 
appropriately trained personnel. 
The lyophilized vial 1 (containing the NeoBOMB1 peptide) shall be directly reconstituted with 
the 68GaCl solution in ultrapure HCl provided by a 68Ge/68Ga generator. After addition of the 
suitable volume of reaction buffer (vial 2) and heating at 95°C for 7 minutes, the 68Ga-labelled 
product is ready to use. 
68Ga eluate should be obtained from an approved commercial 68Ge/68Ga generator that has 
been eluted within the past 4 hrs. 

 
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The recommended activity to be administered is 3 MBq/Kg (± 10%), but not more than 250 
and not less than 150 MBq.  
Refer to Appendix 1 for instruction on the radiolabelling procedure and dispensing [68Ga]-
NeoBOMB1, cautionary notes, analytical controls and stability of the radiolabelled product. 
 
 
5.3 Dose modifications 
Not applicable 
 
5.4 Concomitant medication 
 
Patients can be under active systemic treatment such as anti-cancer therapy or hormonal 
therapy. However, the IP administration should be done at least 72 hours after administration 
of chemotherapy, to allow for the resolution of any acute side effects.   Chemotherapy 
administration or the start of a new anti-cancer therapy should also be held until 48hrs after IP 
administration.    
 
Regional/local radiation should be completed at least 2 weeks before administration of IP. Focal 
radiation therapy is allowed after discussion with the study medical monitor.  
 
The participation of patients on treatment with check-point inhibitors should be discussed with 
the study medical monitor, to assess concurrent adverse events and side effects prior to 
administration.  
 Any other allowed concomitant prescribed medications should be discontinued 2h before and 
until 4h after administration of [68Ga]-NeoBOMB1. 
 
5.5 Labelling 
 
Primary and Secondary packaging for the IMP will be prepared according to Annex 13 of GMP 
(Good Manufacturing Practice) European directive (Eudralex Volume 4), The information that 
will be included in the final labels are reported in the examples below in English. 
As per guidelines, labels of the primary and secondary packaging will be translated in the 
investigational site local language. 
 
Primary Packaging (powder and buffer vial): 
 
 
NeoBOMB1 Powder vial 
For clinical trial use only. Intravenous use after radiolabelling 
Powder for radiopharmaceutical preparation of 68Ga-NeoBOMB1 
One vial of powder containing 50µg of NeoBOMB1. 
EXP: mm/yyyy 
 
 
Lot: xxx 
Store in a refrigerator 
EudraCT number: 2017-003432-37 
Patient Number: xxx 
Sponsor:   
 
 
Manufacturer: 
Advanced Accelerator Applications  
 
International S.A. 
 
 
 
 
 
 
 
 ITALY 

 
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Secondary Packaging (outer box) 
 
 
 
5.6 Handling and storage of IMP at the Site and IMP Accountability 
 
The kit for the preparation of [68Ga]-NeoBOMB1 should be stored upon receipt at 5°C ± 3°C in 
a temperature-controlled refrigerator.  
Regulation on how medication labelled with „For clinical trial use only” is managed: 
• 
Dispensary on pharmacy/investigator (if applicable) 
• 
Written receipt 
• 
Storage at the trial centers 
• 
Documentation of the dispensing to the patients and their usage 
• 
Return of unused medication and empty containers 
• 
Procedure and documentation of the return to the Sponsor or the destruction of 
remainders 
 
The Investigators will be responsible for ensuring the correct storage and sufficient stocks of 
the IMP and comparative drug at the trial centres. The Investigator bears the responsibility for 
the proper storage in a secure location at the site which means in a lockable cabinet with 
restricted access to the Investigator(s) and authorized site staff. Personnel having access to 
the IMP will be listed on the Authorization and Delegation log in the Investigator Site File (ISF). 
The Investigators will ensure that the IMP is only used according to this protocol. The 
Investigator will be responsible for the Drug Accountability log. Drug accountability will be 
noted by a monitor during site visits and at the completion of the trial. The Drug manufacturer 
will provide the clinical trial centre with appropriate forms to document shipments, receipt and 
return (or destruction) of the product. 
Buffer vial 
For clinical trial use only 
Reaction buffer solution for radiopharmaceutical preparation of 68Ga-
NeoBOMB1. Intravenous use after radiolabelling 
EXP: mm/yyyy 
 
 
Lot: xxx 
Store in a refrigerator 
EudraCT number: 2017-003432-37 
Patient Number: xxx 
Sponsor:   
 
 
Manufacturer: 
Advanced Accelerator Applications 
 
International S.A. 
 
 
 
 
 
 
 
 ITALY 
NeoBOMB1 50 µg, kit for the radiopharmaceutical 
preparation  
For clinical trial use only 
Intravenous use after radiolabelling. For single use. 
Refer to the study protocol for directions for use 
One vial of powder contains 50µg of NeoBOMB1. 
EXP: mm/yyyy 
 
 
Lot: xxx 
Store in a refrigerator. 
After radiolabelling, store below 25°C 
EudraCT number: 2017-003432-37 
Patient Number: xxx 
Sponsor:   
 
 
Manufacturer: 
Advanced Accelerator Applications 
 
International S.A. 
 
 
  
Investigator: xxx 
 
 
 Italy 

 
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Unused kits for preparation of [68Ga]-NeoBOMB1 will be returned to the manufacturer or 
destroyed as per the local procedures. 
Based on the stability tests performed, the NeoBOMB1 kit can be stored upon receipt at 5°C ± 
3°C until the expiry date stated on the labels. 
 
 
5.7 Subject compliance 
 
Due to the nature of the drug, patient’s compliance about dosing is of no concern. 
 
6 Safety Definitions and Reporting Requirements 
 
Safety assessments will consist of monitoring and recording AEs, including SAEs.  
  
6.1 Adverse Events (AEs) 
 
An adverse event (AE) is defined as any untoward medical occurrence in the form of signs, 
symptoms, abnormal laboratory findings, or diseases that emerges or worsens relative to 
baseline during a clinical study with an investigational product, regardless of causal 
relationship and even if no investigational product has been administered. 
 
Adverse events include: 
• 
Worsening or increase in frequency or intensity of a pre-existing disease or medical 
condition 
• 
Abnormal laboratory tests 
 
Adverse events do not include: 
• 
Pre-planned interventions/hospitalizations 
• 
Medical or surgical procedures, e.g. surgery, endoscopy, tooth extraction, transfusion. 
However, the event leading to the procedure is an AE. If this event is serious, the 
procedure must be described in the SAE narrative. 
• 
Pre-existing disease or medical condition that does not worsen. 
• 
Diagnosis of progressive disease i.e. increase in tumour load or newly identified 
metastasis/complication during routine diagnostic CT. 
• 
Overdose of either study drug or concomitant medication without any signs or 
symptoms that should be considered only as a specific situation. 
 
All AEs will be reported and recorded from the signature of the ICF. 
 
6.2 Serious Adverse Events (SAEs) 
 
A serious adverse event (SAE) is defined by the International Conference on Harmonization 
(ICH) guidelines as any AE fulfilling at least one of the following: 
• 
Resulted in deaths 

 
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• 
Was life-threatening – defined as an event in which the subject was, in the judgment of 
the investigator, at risk of death at the time of the event; it does not refer to an event 
that hypothetically might have caused death if it had been more severe 
• 
Required or prolonged hospitalization: i.e. the AE requires at least a 24-hour in-
patient hospitalization or prolongs a hospitalization beyond the expected length of stay. 
Hospital admissions for surgery planned before trial entry, for social reasons or for 
normal disease management (including treatment adjustment) are not to be considered 
as SAE according to this criterion. 
• 
Resulted in persistent or significant disability or incapacity (i.e. a substantial 
disruption of a person’s ability to conduct normal life functions) 
• 
Was a congenital anomaly or birth defect: i.e. an adverse outcome in a child or 
foetus of a subject’s partner exposed to the study drug, before conception or during 
pregnancy. 
• 
is medically significant, i.e. an event may not be immediately life-threatening or result 
in death or hospitalization but may jeopardize the subject or may require intervention 
to prevent one of the other outcomes listed in the above definition should also usually 
be considered as serious. 
 
Inpatient hospitalization is defined as an overnight stay in a hospital unit and/or emergency 
room that includes at least one night (midnight to 06:00 AM).  
The following is not considered as a SAE and should be reported as an AE only: 
• 
Treatment of an emergency or outpatient basis for an event not fulfilling the definition 
of seriousness given above and not resulting in hospitalization 
 
The following reasons for hospitalization are not considered as AEs or SAEs: 
• 
Standard monitoring of a pre-existing disease or medical condition that did not worsen, 
e.g. hospitalization for coronary angiography in a subject with stable angina pectoris 
• 
Elective treatment of a pre-existing disease or medical condition that did not worsen, 
e.g. hospitalization for chemotherapy for cancer, elective hip replacement for arthritis 
• 
Hospitalization for cosmetic elective surgery, social and/or convenience reasons 
 
 
6.3 Adverse Drug Reaction (ADR) & Unexpected Adverse Drug Reaction 
 
An ADR is any noxious and unintended response to an IMP related to any dose with at least 
a reasonably possible causal relationship with the IMP. Briefly, an ADR is an AE which is 
possibly related to IMP by either the investigator or the study sponsor. 
. 
 
6.4 Suspected Unexpected Serious Adverse Reaction (SUSAR) 
 
Unexpected ADR means the nature or severity of which is not consistent with the applicable 
product information available for the IMP. Expected ADRs are listed in the Investigator’s 
Brochure  

 
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A SUSAR is an adverse event, the nature or severity of which is not consistent with the 
applicable information available in the reference documents available for the IMP and is 
regarded as serious, and has at least possible relationship with the IMP. 
 
6.5 Pregnancy 
 
To avoid the application of the study medication during pregnancy, pregnancy tests will be 
performed at Screening and prior to injection. Any pregnancy that occurs during study 
participation must be reported to the investigator/sponsor immediately (no later than SAEs 
reporting timelines). If a pregnancy should be confirmed after informed consent has been 
obtained but prior to the initiation of the study drug, the patient must be excluded from the trial.  
The pregnancy must be followed up to determine outcome (including premature termination) 
and status of mother and child. Pregnancy complications (including spontaneous abortions) 
and elective terminations must be reported as an AE or SAE. 
Any SAE occurring in association with a pregnancy brought to the investigator’s attention after 
the subject has completed the study and considered by the investigator as possibly related to 
the IMP, must be promptly reported to the sponsor. 
As the consent for the study does not cover the consent for the follow-up of the pregnancy, a 
separate consent must be obtained. 
 
6.6 Severity of adverse events / Grading 
 
Intensity of all adverse events will be graded according to the Toxicity Grading Scale vaccine 
clinical trials (Appendix 2) and reported in detail in the Case Report Form (CRF). 
Adverse events not listed in the Toxicity Grading Scale vaccine clinical trials should be graded 
as follows: 
 
 
CTC grade 
Equivalent to  
Definition 
Grade 1 
Mild 
Discomfort noticed but no disruption of normal daily activity 
and does not require mandatory corrective/symptomatic 
treatment 
Grade 2 
Moderate 
Discomfort sufficient to reduce or affect daily activity; no 
treatment or medical intervention (other than minimal) is 
indicated although this could improve the overall wellbeing 
or symptoms of the patient.  
Grade 3 
Severe 
Inability to work or perform normal daily activity; treatment 
or medical intervention is indicated to improve the overall 
wellbeing or symptoms; delaying the onset of treatment is 
not putting the survival of the patient at direct risk.  
Grade 4 
Life-
threatening / 
disabling 
An immediate threat to life or leading to a permanent 
mental or physical condition that prevents work or 
performing normal daily activities; treatment or medical 
intervention is required to maintain survival.  

 
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Grade 5 
Death 
AE resulting in death  
 
 
6.7 Relationship to study drug 
 
The assessment of relationship of adverse events to the administration of IMP is a clinical 
decision based on all available information and considering all relevant factors such as (but 
not limited to) the underlying indication, coexisting diseases, concomitant medication, etc. at 
the time of the completion of the case report form. 
Is there a reasonable possibility that the study drug caused the event?  
Answer YES (definitely, probably or possibly related) if one or more of the following criteria 
apply:  
• 
The event follows a reasonable temporal sequence from administration of study drug.  
• 
The event could not be reasonably attributed to the known characteristics of the 
patient’s clinical state, environmental or toxic factors or other modes of therapy 
administered to the patient.  
• 
The event follows a known pattern of response to study drug.  
 
The event disappears or decreases on cessation or reduction in dose of the study drug. (It 
should be noted that in some situations an AE will not disappear or decrease in intensity upon 
discontinuation of study drug despite other clear indications of relatedness).  
Otherwise answer NO (unlikely, probably not related or definitely not related). 
 
 
 
6.8 Reporting procedures for AEs 
 
A special section is designated to adverse events in the CRF where the following details must 
be entered:  
• 
Type of adverse event (diagnosis or syndrome; if not known signs or symptoms) and 
brief description (including context of occurrence) 
• 
Start (date)  
• 
End (date)  
• 
Severity (mild, moderate, severe, life-threatening/disabling, death)  
• 
Serious (no / yes)  
• 
Outcome (resolved, ongoing, ongoing – improved, ongoing – worsening) and recovery 
date 
• 
Action taken (none, study medication dose reduced, study medication interrupted, 
study medication discontinued, medication therapy, surgical procedure, hospitalization, 
other)  
• 
Relation to study drug (possibly, probably or definitely related or unlikely, probably not 
related or definitely not related)  
• 
Treatment date with the IMP (in order to estimate the time to onset) 

 
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• 
Patients relevant medical history and/or concomitant treatments that may provide 
alternative explanation regarding the AEs occurrence. 
 
 
6.9 Reporting procedures for SAEs  
 
When an SAE is made known to the Principal Investigator (PI) or other site personnel, it must 
be reported to AAA Pharmacovigilance within the best timelines and no more than 24 hours 
(one calendar day) of knowledge of the event. 
   
The responsibilities of the PI include but are not limited to: 
• 
Identifying the SAE (detailed description) and providing the criteria of seriousness, 
• 
Assessing causality/relationship of the SAE to investigational product, 
• 
Determining the severity/intensity according to the protocol and event outcome, 
• 
Determining the event onset and resolution dates, 
• 
Maintaining adequate documentation of the SAE and all communications relating to the 
event including communications with the subject, treating physician, AAA 
Pharmacovigilance, CRO 
 
The SAE reporting process is described below: 
• 
Complete an SAE report form.  The SAE report form must be documented in English 
and any supporting documentation (e.g. event narrative or discharge summary) must 
be briefly summarized in English in the SAE report.  Unless otherwise requested by 
AAA Pharmacovigilance, only death certificates and autopsy reports may be submitted 
as separate documents. Discharge summary translated in English may also been 
provided upon Sponsor (AAA) request 
• 
Provide as much information as is known at the time the initial report is submitted to 
AAA Pharmacovigilance.  The elements required to make an initial assessment of the 
event to meet reporting obligations to health authorities are: 
✓ Site number (4-digit) and subject number (3-digit) and subject initials (if local 
privacy laws allow), 
✓ Serious event description plus all seriousness criterion that apply (e.g., 
hospitalization, etc), 
✓ Relationship to investigational product (causality assessment), 
✓ Severity/intensity grade as available, 
✓ Start date of event, 
✓ Investigational product administration details (i.e., dose, regimen, and 
therapy dates), 
✓ Outcome at time of initial reporting 
✓ Reporter name, Investigator name, phone number, and email address. 
• 
Fax or email the completed SAE report form to AAA Pharmacovigilance using the fax 
number or email address located on the SAE report form or in the SAE Completion 
Guidelines (Fax: 
, E-mail:
) . 

 
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Site personnel will retain a record of faxed/emailed SAE report forms in the site file; i.e., 
print the confirmation of successful transmission from the fax machine or a copy of sent 
email.  If a fax print-out is unavailable, a written notation of fax date and time on the 
coversheet is acceptable. 
• 
Fax/email relevant follow-up information to AAA Pharmacovigilance, within 24 hours of 
receiving the information, via a Follow-up SAE report form, including, but not limited to: 
✓ Start and stop dates of event, 
✓ Action(s) taken regarding investigational product(s), 
✓ Event outcome, 
✓ Discharge summary (e.g., diagnostic test reports, x-ray reports, discharge 
summaries or autopsy report, if applicable to the SAE(s) being reported), 
NOTE:  The Investigator and other site personnel must ensure subject confidentiality is 
maintained when reporting SAEs to AAA Pharmacovigilance. The site should review the 
supporting documentation to ensure complete redaction of any subject identifying information 
prior to forwarding to AAA Pharmacovigilance. 
 
 
6.10  Reporting to the competent authorities and IRB/IEC 
 
The Sponsor or representative will assume responsibility for appropriate reporting of 
Suspected Unexpected Serious Adverse Reactions (SUSARs) and any new safety data which 
jeopardize the safety of any volunteer to the Competent Authorities (CA) and Independent 
Ethics Committee(s)/Institutional Review Board(s) (IEC/IRB) according to local laws and 
regulations. 
The Sponsor will inform CA, IRB/IEC, and Investigators of “findings that could adversely affect 
the safety of subject and impact the conduct of the study or alter the IRB/IEC’s 
approval/favourable opinion to continue the study”. The Sponsor will inform about adverse 
events from other trial sites, other clinical studies with the same product, or from post-
marketing setting as applicable, depending on the stage of development of the product, which 
are both serious and unexpected and whose causal relationship with the administered product 
was considered as definitely, possibly or probably related by the Investigator. 
Copies of safety reports should be kept in the Investigator file as well as inserted into the 
relevant Investigator Brochure. In addition, all correspondence relating to their notification to 
the Competent Authorities and IRB/IEC should be maintained in the Investigator file. 
 
6.11 Adverse Event Reporting Period 
 
All AEs will be reported and recorded from the signature of the ICF. 
Investigators will seek information on AEs at each patient contact throughout the trial. All AEs, 
whether reported by the patient or noted by study personnel, will be recorded in the patient’s 
medical record and on the Adverse Event part of the application day Case Report Form (CRF).  

 
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After informed consent has been obtained all AEs and SAEs regardless of relationship to 
the study drug will be reported until FU3 or until the event has resolved to baseline grade or 
better, the event is assessed as stable by the investigator, the patient is lost to follow-up, or 
the patient withdraws consent.  
After FU3, investigators should report any deaths, SAEs, or other AEs of concern that are 
believed to be related to prior treatment with the study drug.  
Any Serious Adverse Event (SAE) that is ongoing at the time of FU3 should be followed-up 
until resolved.  
 
6.12 Annual Safety Report 
 
Once per year, the sponsor or PI will supply a report on the safety of trial subjects with all 
available relevant information concerning patient safety during the reference period to the 
competent authorities of all other member states of the Europe where the trial is being 
conducted. This report will also be supplied to the responsible ethics committee. 
The annual safety report will be compiled according to the corresponding ICH guideline E2F 
”Development Safety Update Report – DSUR“ 
The data lock point for the DSUR will be the day prior to the anniversary of the date of the first 
authorization of this clinical trial. 
The sponsor will supply the report within 60 from the data-lock point.  
 
 
 
7 Statistical considerations 
 
7.1 Sample Size & Randomization 
 
The primary objective of the trial is to assess preliminary targeting properties of [68Ga]-
NeoBOMB1.  Data for this objective will be reported descriptively therefore no formal statistical 
sample size calculation is feasible.  In addition, no randomization is required due to the study 
design.  It is anticipated that 50 patients with malignancies known or suspected to overexpress 
GRPR will be recruited in the trial and will undergo application of [68Ga]-NeoBOMB1 and PET-
CT imaging.  It is expected that a large proportion of these patients will be GRPR positive 
according to histopathology / cytology data but that patients will also be recruited whose 
tumours do not show GRPR expression by histopathology / cytology data.  This will allow 
calculation of preliminary diagnostic characteristics and the sample size should allow 
reasonable precision around estimations of targeting properties.  For example, if a patient level 
sensitivity of 83.3% is observed (for e.g. if 25 patients had lesions detected by [68Ga]-
NeoBOMB1 imaging out of 30 patients in the trial with GRPR positive histopathology / cytology) 
the 95% CI around this would be 66.4% to 92.7%. 
The overall sample size of 50 patients will be fixed to ensure 10 patients are recruited within 
each of the tumour types included in the trial.  Although it won’t be possible to make strong 
conclusions within the tumour types, this should ensure that a reasonable number of GRPR 

 
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positive patients are available within each tumour type and this will allow initial estimates of 
diagnostic properties to be made and will ensure each tumour type is fairly represented. 
Ten patients will be recruited to the dosimetry sub-population of the trial.  This is considered 
sufficient to obtain data on dosimetry, biodistribution and dose-limiting critical organs.  Data 
from all 50 patients in the trial will be used to assess all other study objectives. 
7.2 Statistical Design, Method and analytical Procedures and Definition 
of Populations 
 
The Full Analysis Set (FAS) will consist of all patients who enter the study and receive the 
[68Ga]-NeoBOMB1 dose.  The safety set in this case is identical to the FAS and so will not be 
defined as a separate set. The Per Protocol (PP) set consists of all patients of the FAS set 
who complete the study according to the protocol with no major protocol violations. All analyses 
will primarily be performed on the FAS, select analyses may be repeated on the PP set if there 
are sufficient violations to warrant it and deviation of results by using the PP set will be 
discussed. All data will be listed and summary tables of the data will be given.  
Statistical methods will be detailed in the Statistical Analysis Plan (SAP). 
The primary focus of the statistical analysis will be on descriptive statistics and graphical 
presentations of data.  Continuous variables will be presented as number of non-missing 
values, mean, standard deviation, median, minimum, maximum and quartiles. For categorical 
variables, descriptive statistics will include counts and percentages per category. Confidence 
intervals will be computed when appropriate. Continuous variables will be compared where 
relevant using the most appropriate test such as paired analysis Mann-Whitney-Wilcoxon U test 
or paired analysis Student’s t test. Proportions will be compared using the appropriate test 
among Chi squared test, Fisher exact test or McNemar test. Pearson’s or Spearman linear 
regression analysis will be used to explore potential relationships between two continuous 
variables as appropriate.  Any hypothesis testing that is performed will be interpreted as 
exploratory and no emphasis will be placed on nominal significance levels. 
No adjustment for multiplicity will be applied and missing data will not be replaced. 
 
All data presentations will be presented primarily by the overall population but may also be 
repeated split by tumour type where relevant. Some presentations will also be repeated split by 
whether or not the patient was found to have tumours bearing GRPR expression according to 
cytology and/or histopathology findings. 
 
 
7.3 
Efficacy Analysis 
 
Primary endpoint: 
• 
The preliminary targeting properties of [68Ga]-NeoBOMB1 will be assessed by 
summaries of the number and location of lesions identified by PET, SUV values per 

 
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lesion, tumour background ratio of [68Ga]-NeoBOMB1 and the percentage of injected 
dose reaching the target presented split by GRPR positive and negative patients.  
Tumour uptake will be evaluated by Standard Uptake Value. SUVmean and SUVmax will 
be determined and summarized descriptively. 
• 
The tumour-background ratio of [68Ga]-NeoBOMB1 and the percentage of injected 
dose reaching the target will be calculated using the acquired images resulting in time-
activity curves (TACs) with quantitative fractions of administered activity and 
summarized descriptively. 
Secondary endpoints: 
• 
The [68Ga]-NeoBOMB1 bio-distribution, pharmacokinetics, dosimetry and absorbed 
dose in critical organs will be determined by calculation of TACs measured by a Nal 
gammacounter from blood and urine and stability will be analysed using HPLC 
measurements. Regions of interest (ROI) for critical organs and tumour lesions will be 
drawn using the acquired images resulting in time-activity curves with quantitative 
fractions of administered activity. Dosimetry calculations will be issued from the 
analyses of organs receiving the highest dose, identified visually. ROI will be placed 
over these organs to determine relative radiotracer uptake calculated as a percentage 
of the injected dose per gram of tissue (%ID/g). Tissue activity curves will be generated 
from the amount of radioactivity in one given tissue at a given moment considering renal 
excretion activity. Tissue ACs will be fitted to mono- and bi-exponential curves to yield 
cumulative activities. Urine samples 0-2h and 4h post-injection will be collected to 
complete dosimetry and biodistribution assessments. The absorbed dose (μGy/MBq) 
will be transformed into formal biological equivalent dose for radiation exposure 
(μSv/MBq) to finally yield an effective radiation dose, a factor between others that could 
help providing an estimation of total danger to the whole organism. Effective radiation 
dose will be summarized descriptively. 
• 
Tumour uptake will be evaluated by Standard Uptake Value. SUVmean and SUVmax will 
be determined and summarized descriptively. 
• 
Number of observed tumour lesions and localization in PET/CT will be summarized 
descriptively overall and split by GRPR positive and negative patients, as well as by 
tumour type, and will be compared to the number of observed lesions and localization 
in a comparable conventional imaging.   
• 
Positive and negative lesions by the two imaging techniques will be cross tabulated 
overall and also by localization area on a lesion level and a patient level.  This will also 
be repeated splitting by GRPR positive and negative patients and also by primary 
tumour type of patients in the trial. 
o On a lesion level overall, positive and negative agreement of [68Ga]-NeoBOMB1 
will be calculated as follows: 
▪ 
Overall agreement = 100% x (Double positive + Double negative) / total 
number of patients who underwent both imaging procedures 
▪ 
Positive agreement = 100% x Double positive / (Double positive + 
Comparator single positive) 

 
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▪ 
Negative agreement = 100% x Double negative / (Double negative + 
Comparator single negative) 
The McNemars test may also be performed to assess level of discordance 
between the two imaging techniques where appropriate, acknowledging issues 
with lack of independence of observations on a lesion level. 
o On a patient level positive agreement of [68Ga]-NeoBOMB1 will be defined as 
the proportion of patients with at least one lesion detected by conventional 
imaging (i.e. all patients included in the trial) that also have at least one lesion 
detected by [68Ga]-NeoBOMB1. 
• 
[68Ga]-NeoBOMB1 PET preliminary diagnostic performance relative to cytology and/or 
histopathology findings from archival and/or recent biopsy specimens will be assessed 
primarily on a patient level, but also on a lesion level for lesions with associated biopsy 
data available.   
o On a patient level, patients with at least one positive PET imaging lesion 
identified versus those without any PET imaging lesions identified will be cross-
tabulated with whether or not they have at least one biopsy with GRPR 
expression identified.  Sensitivity and specificity values will be calculated as 
appropriate. 
o 
On a lesion level, positive and negative PET imaging lesions will be cross-
tabulated with their GRPR positive or negative status according to biopsy data 
and sensitivity and specificity values will be calculated as appropriate.  
Appropriate tests of association may also be performed if relevant.  
 
Potential relationships between [68Ga]-NeoBOMB1 PET targeting properties and 
cytology and/or histopathology findings may also be explored using alternative 
endpoints where appropriate.  For example, continuous measures of GRPR expression 
may be correlated against each patient proportion of conventional imaging lesions also 
detected by [68Ga]-NeoBOMB1 PET imaging using scatterplots and simple linear 
regression models. 
7.4 
Safety Analysis 
 
Safety evaluations on the FAS will be based on the incidence, type, severity and consequences 
(e.g. study discontinuation) of an adverse event (AE) as well as on clinically significant changes 
in the patient's physical examination, ECGs, vital signs, and clinical laboratory results.  ECG 
parameters will include heart rate (HR), RR interval, PR interval, QRS width and QTc interval.  
Statistical analysis includes descriptive tabulation using measures which are absolute and 
relative frequencies for categorical data and means, standard deviations, medians and 
interquartile ranges for continuous data for observed values as well as for changes from 
baseline in continuous parameters at each measuring time.  Clinical laboratory data, ECGs 
and vital signs will also be presented graphically in terms of box plots of absolute values over 
time and changes from baseline over time.  Clinical laboratory data will be summarized with 
respect to the normal ranges of values provided by the laboratory and with respect to pre-
defined levels of change in these values.  

 
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All original AE/SAE terms will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Adverse events will be listed on an individual basis and will be summarized by 
System organ classes and preferred terms will be used in the analyses.   Patients with more 
than one adverse event within a particular SOC and PT will be counted only once for that SOC 
and PT.  The type and incidence of AEs/SAEs, as well as severity and relatedness to the 
investigational product will be tabulated. 
 
7.5 The treatment of missing, unused or spurious Data, including Drop-
outs and Withdrawals 
 
No specific procedures for handling of missing, unused and spurious data will be pre-
determined. 
 
 
8 Documentation 
 
The accomplishments of the study in agreement with the GCP-guidelines and the 
investigational plan as well as the accuracy of all data documented in the e-CRF are the 
responsibility of the Investigator. All data of this study must be recorded on the e-CRF by 
appropriate authorized persons. This also includes data of patients who dropped-out of the 
study. 
The Investigator records the participation on a special identification list of patients. This list 
gives the possibility for a later identification of the patients and contains the patient number, 
full name, date of birth and the date of the enrollment into the study. The identification list of 
patients remains in the study centre after the closure of the study. Additionally, the participation 
of the patient in this clinical study must be recorded in the patient`s medical record 
(investigational medicinal product, number of patient or randomization, start and end of the 
study). 
It must be assured that all persons authorized for e-CRF entries can be identified. A list with 
signatures and identification codes of the persons must be archived in the ISF and Trial Master 
File (TMF). Furthermore, logs according to ICH E6 (e.g. Signature/Delegation/Screening/Drug 
Accountability log) will be implemented and maintained by the Investigator. 
 
8.1 Recording of Data 
 
Data collection for each patient is done using a e-CRF. This e-CRF is filled up by the 
Investigator, according to the completion guidelines. 
For each patient enrolled, a eCRF must be completed, signed and dated by the Investigator 
or by his/her authorized designee(s) according to the Signature/Delegation Log. This also 
applies to subjects failing to complete the study (Drop-Outs). 
The Investigator assures that all data are recorded immediately, are complete, correct and in 
agreement with the patient`s medical records. 

 
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A copy remains at the Investigator and will be kept for 15 years. 
 
 
 
8.2 Trial Master File 
 
The paper-based/electronic TMF, established at the beginning of the trial and secured in a 
safe place, contains all essential documents that demonstrate that the trial is conducted in 
accordance with regulatory requirements and ICH GCP. All documents will be maintained and 
updated as appropriate throughout the trial. Previous versions of the documents must be 
retained in the TMF and will be clearly labelled as outdated. The TMF is archived at the end of 
the study for 15 years.  
 
8.3 Investigator Site File 
 
The paper-based ISF, established at the beginning of the trial will be secured in a safe place 
(the file is provided to the sites at the site initiation visit). It contains all essential documents 
maintained by the PI(s). All documents will be maintained and updated as appropriate 
throughout the trial. Previous versions of the documents must be retained in the ISF and will 
be clearly labelled as superseded. Within each monitoring visit, the ISF will be checked for 
actuality and completeness in accordance to the formalities by the Clinical Research Associate 
(CRA). After completion or discontinuation of the study the ISF must be kept for 15 years. 
 
8.4 Storage of Data 
 
8.4.1 Storage Duties of the Sponsor 
 
The Sponsor must keep all study-relevant documents of the clinical study after completion or 
discontinuation of the study for a minimum of 15 years in the TMF. 
 
8.4.2 Storage Duties of the Investigator 
 
The Investigators must keep all records and documents, which are related with the study or 
the allocation of investigational medicinal products (e.g. data entry form, consent form, list of 
the allocations of investigational medicinal products and further relevant documents), for a 
minimum of 15 years in the ISF. 
Medical records and other original data must be kept for 30 years. 
 
 
 
9 Quality Control and Quality Assurance 
 
Training, monitoring and audits are performed for quality assurance reasons within this clinical 
study. Monitoring and auditing procedures developed or endorsed by the Sponsor will be 

 
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adhered to, to comply with ICH-GCP guidelines and local legal requirements to ensure 
acceptability of the study data.  
 
9.1 Training 
 
The Sponsor is responsible for selecting the Investigator(s)/Institution(s). Each Investigator 
should be qualified by training and experience and should have adequate resources. Everyone 
involved in conducting a trial should be qualified by education, training and experience to 
perform his or her respective task(s) (see ICH GCP E6). 
Investigators will have to have experience in the field of clinical imaging studies.  
 
9.2 Clinical Monitoring 
 
The trial sites will be monitored by CRAs to ensure the quality of the data collected. The 
objectives of the monitoring procedures are to ensure that the trial subject’s safety and rights 
as a study participant are respected. In addition, it is to ensure accurate, valid and complete 
data are collected, and that the trial is conducted in accordance to the trial protocol, the 
principles of GCP and local legislation. 
All Investigators agree that the CRA regularly visits the trial site and assure that the CRA will 
receive appropriate support in their activities at the trial site, as agreed in separate contracts 
with each trial site. The ICF includes a statement that the CRA has the right – while observing 
the provisions of data protection legislation – to compare CRFs with the trial subject’s medical 
records (doctor’s notes, ECGs, laboratory printouts etc.). The Investigator will secure access 
for the CRA to all necessary documentation for trial-related monitoring.  
A study specific monitoring plan will be established and the study will be monitored with the 
agreed plan. 
 
9.3 Auditing 
 
Regulatory authorities, the ethics committees, and Sponsor’s delegates may perform on-site 
inspections or audits, for which the Investigator must grant direct access to all data and must 
provide support at all times. 
The aim of an audit is to verify the validity, accuracy and completeness of data, to establish 
the credibility of the clinical trial, and to check whether the trial subject’s rights and trial subject 
safety are being maintained. The Sponsor may assign these activities to persons otherwise 
not involved in the trial (Auditors). These persons are allowed access to all trial documentation 
(especially the trial protocol, CRFs, trial subjects’ medical records, drug accountability 
documentation, and trial-related correspondence). 
After each external audit an audit-certificate by the Auditor must be delivered to the 
Investigator. This certificate must be kept in the ISF to evidence the audit to the regulatory 
authorities in the case of an inspection by them. The audit-report is delivered to the Sponsor 
of the study. An audit-certificate will be attached to the final report at the end of the study. 
Additionally, audits and inspections by regulatory authorities may be performed. 

 
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All persons conducting audits undertake to keep all trial subject data and other trial data 
confidential. 
 
 
10 Reporting 
 
10.1 Final Study Report 
 
All information regarding this clinical study must be kept in confidence. The statistical analysis 
and the integrated final study report will be prepared according to ICH E6 and finalized within 
12 months after the Last Patient Last Visit (LPLV) took place. The final study report will be 
reviewed and signed by the Sponsor, the Coordinating Investigator and all further responsible 
persons. All information in that report is strictly confidential.  
 
10.2 Publication/Data sharing Policy 
 
The Investigator/Institution will not publish the results of the trial without the prior written 
consent of the Sponsor, which permission shall not be unreasonably withheld.  If the Sponsor 
grants such permission, the Investigator/Institution agrees to submit a copy of any manuscript 
and/or abstract to the Sponsor for review and comment at least 90 days prior to its submission 
for publication.  The Sponsor shall have the applicable 90-day period to respond to the 
Investigator/Institution with any revisions.  Investigator/Institution agrees to delete any 
confidential information identified by the Sponsor at the Sponsor's sole discretion, prior to 
submitting such manuscript and/or abstract for publication.  If reasonably requested by the 
Investigator/Institution, the Sponsor will take reasonable steps to expedite the review process 
to less than the 90-day period to meet Investigator's/Institution's publication deadlines, but the 
Sponsor is under no obligation to expedite the review process.  Upon notification by the 
Sponsor that such review has been completed, Investigator/Institution may submit the 
manuscript and/or abstract for publication after deleting any confidential information identified 
by the Sponsor. 
 
 
11 Ethical and Regulatory Aspects 
 
11.1 Good Clinical Practice and Declaration of Helsinki 
 
The procedures set out in this study protocol are designed to ensure that the Sponsor and the 
Investigator abide the principles of ICH E6 recommended for adaptation in June 2015 by the 
ICH Steering Committee and according to the Declaration of Helsinki of 2013 concerning the 
conduct, evaluation and documentation of the study. The study will also be performed adhering 
the local legal conditions and requirements. Each Investigator must confirm this by signing the 
study protocol. 

 
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11.2 Approval of the Study  
 
Prior to study start, the study protocol and/or other appropriate documents will be submitted to 
the relevant ECs and CAs for approval. Approval from all concerned ECs and CAs must be 
obtained before starting the study. 
 
11.3 Insurance 
 
During their participation in the clinical trial the patients will be insured as defined by legal 
requirements. The sponsor is providing insurance to indemnify (legal and financial coverage) 
the investigator/trial centre against claims arising from the study, except for claims that arise 
from malpractice and/or negligence. The compensation of the subject in the event of study-
related injuries will comply with the applicable regulations. 
 
11.4 Confidentiality 
 
All local legal requirements regarding data protection will be adhered to. All study findings and 
documents will be regarded as confidential. The Investigator and members of the research 
team must not disclose any information without prior written approval from the Sponsor.  
The pseudonymity of patients participating must be maintained. Throughout documentation 
and evaluation, the patients will be identified on CRFs and other documents by a patient IDs. 
Documents that identify the patient personally (e.g., the signed informed consent, patient 
identification list) must be maintained in confidence by the Investigator. The patients will be 
informed in the ICF that all study findings will be stored on paper and handled in strictest 
confidence. 
 
 
 
12 Amendments 
 
Amendments must be submitted to the appropriate CAs and ECs. Substantial amendments 
may be implemented only after CA/EC approval has been obtained. Urgent amendments that 
are intended to eliminate an apparent immediate hazard to subjects may be implemented prior 
to receiving CA/EC approval.  However, approval must be obtained as soon as possible after 
implementation. Therefore, the sponsor must inform the CA and the EC concerned of the new 
events, the measures taken and their plan for further action as soon as possible.  
 
 

 
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14 Supplements/Appendices 
 
14.1  Appendix 1: Toxicity Grading Scale vaccine in clinical trials 
 
A. Tables for Clinical Abnormalities  
Local Reaction to 
Injectable Product 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Pain 
Does not 
interfere with 
activity 
Repeated use of 
non-narcotic pain 
reliever > 24 hours 
or interferes with 
activity 
Any use of 
narcotic pain 
reliever or 
prevents daily 
activity 
Emergency room 
(ER) visit or 
hospitalization 
Tenderness 
Mild 
discomfort to 
touch 
Discomfort with 
movement 
Significant 
discomfort at 
rest 
ER visit or 
hospitalization 
Erythema/Redness * 2.5 - 5 cm 
5.1 - 10 cm 
> 10 cm 
Necrosis or 
exfoliative 
dermatitis 
Induration/Swelling ** 2.5 - 5 cm and 
does not 
interfere with 
activity 
5.1 - 10 cm or 
interferes with 
activity 
> 10 cm or 
prevents daily 
activity 
Necrosis 
* In addition to grading the measured local reaction at the greatest single diameter, the measurement should be recorded as 
a continuous variable. 
** Induration/Swelling should be evaluated and graded using the functional scale as well as the actual measurement.  
 
 
Vital Signs * 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Fever (°C) ** 
           (°F) * 
38.0 – 38.4 
100.4 – 101.1 
38.5 – 38.9 
101.2 – 102.0 
39.0 – 40 
102.1 – 104 
> 40 
> 104 
Tachycardia - 
beats per minute 
101 – 115 
116 – 130 
> 130 
ER visit or 
hospitalization for 
arrhythmia 
Bradycardia - 
beats per 
minute*** 
50 – 54 
45 – 49 
< 45 
ER visit or 
hospitalization for 
arrhythmia 
Hypertension 
(systolic) - mm 
Hg 
141 – 150 
151 – 155 
> 155 
ER visit or 
hospitalization for 
malignant 
hypertension 

 
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Hypertension 
(diastolic) - mm 
Hg 
91 – 95 
96 – 100 
> 100 
ER visit or 
hospitalization for 
malignant 
hypertension 
Hypotension 
(systolic) – mm 
Hg 
85 – 89 
80 – 84 
< 80 
ER visit or 
hospitalization for 
hypotensive 
shock 
Respiratory Rate 
– breaths per 
minute 
17 – 20 
21 – 25 
> 25 
Intubation 
* Subject should be at rest for all vital sign measurements. 
** Oral temperature; no recent hot or cold beverages or smoking. 
*** When resting heart rate is between 60 - 100 beats per minute. Use clinical judgement when characterizing bradycardia 
among some healthy subject populations, for example, conditioned athletes.  
 
 
Systemic 
(General) 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Nausea/vomiting No interference 
with activity or 1 - 
2 episodes/24 
hours 
Some 
interference with 
activity or > 2 
episodes/24 
hours 
Prevents daily 
activity, requires 
outpatient IV 
hydration 
ER visit or 
hospitalization for 
hypotensive 
shock 
Diarrhea 
2 - 3 loose stools 
or < 400 gms/24 
hours 
4 - 5 stools or 
400 - 800 gms/24 
hours 
6 or more watery 
stools or > 
800gms/24 hours 
or requires 
outpatient IV 
hydration 
ER visit or 
hospitalization 
Headache 
No interference 
with activity 
Repeated use of 
non-narcotic pain 
reliever > 24 
hours or some 
interference with 
activity 
Significant; any 
use of narcotic 
pain reliever or 
prevents daily 
activity 
ER visit or 
hospitalization 
Fatigue 
No interference 
with activity 
Some 
interference with 
activity 
Significant; 
prevents daily 
activity 
ER visit or 
hospitalization 
Myalgia 
No interference 
with activity 
Some 
interference with 
activity 
Significant; 
prevents daily 
activity 
ER visit or 
hospitalization 
Systemic 
Illnes 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Illness or 
clinical adverse 
No interference 
with activity 
Some 
interference 
Prevents daily 
activity and 
ER visit or 
hospitalization 

 
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event (as 
defined 
according to 
applicable 
regulations) 
with activity not 
requiring 
medical 
intervention 
requires 
medical 
intervention 
 
 
B.Tables for Laboratory Abnormalities 
The laboratory values provided in the tables below serve as guidelines and are dependent 
upon institutional normal parameters. Institutional normal reference ranges should be 
provided to demonstrate that they are appropriate. 
 
Serum * 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4)** 
Sodium – Hyponatremia 
mEq/L 
132 – 134 
130 – 131 
125 – 129 
< 125 
Sodium – Hypernatremia 
mEq/L 
144 – 145 
146 – 147 
148 – 150 
> 150 
Potassium – Hyperkalemia 
mEq/L 
5.1 – 5.2 
5.3 – 5.4 
5.5 – 5.6 
> 5.6 
Potassium – Hypokalemia 
mEq/L 
3.5 – 3.6 
3.3 – 3.4 
3.1 – 3.2 
< 3.1 
Glucose – Hypoglycemia 
mg/dL 
65 – 69 
55 – 64 
45 – 54 
< 45 
Glucose – Hyperglycemia 
Fasting – mg/dL 
Random – mg/dL 
  
100 – 110 
110 – 125 
  
111 – 125 
126 – 200 
  
>125 
>200 
Insulin 
requirements or 
hyperosmolar 
coma 
Blood Urea Nitrogen 
BUN mg/dL 
23-26 
27 – 31 
> 31 
Requires dialysis 
Creatinine – mg/dL 
1.5 – 1.7 
1.8 – 2.0 
2.1 – 2.5 
> 2.5 or requires 
dialysis 
Calcium – hypocalcemia 
mg/dL 
8.0 – 8.4 
7.5 – 7.9 
7.0 – 7.4 
< 7.0 
Calcium – hypercalcemia 
mg/dL 
10.5 – 11.0 
11.1 – 11.5 
11.6 – 12.0 
> 12.0 
Magnesium – 
hypomagnesemia mg/dL 
1.3 – 1.5 
1.1 – 1.2 
0.9 – 1.0 
< 0.9 
Phosphorous – 
hypophosphatemia mg/dL 
2.3 – 2.5 
2.0 – 2.2 
1.6 – 1.9 
< 1.6 
CPK – mg/dL 
1.25 – 1.5 x 
ULN*** 
1.6 – 3.0 x 
ULN 
3.1 –10 x 
ULN 
> 10 x ULN 

 
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Albumin – Hypoalbuminemia 
g/dL 
2.8 – 3.1 
2.5 – 2.7 
< 2.5 
-- 
Total Protein – 
Hypoproteinemia g/dL 
5.5 – 6.0 
5.0 – 5.4 
< 5.0 
-- 
Alkaline phosphate – increase 
by factor 
1.1 – 2.0 x 
ULN 
2.1 – 3.0 x 
ULN 
3.1 – 10 x 
ULN 
> 10 x ULN 
Liver Function Tests –ALT, 
AST increase by factor 
1.1 – 2.5 x 
ULN 
2.6 – 5.0 x 
ULN 
5.1 – 10 x 
ULN 
> 10 x ULN 
Bilirubin – when accompanied 
by any increase in Liver 
Function Test increase by 
factor 
1.1 – 1.25 x 
ULN 
1.26 – 1.5 x 
ULN 
1.51 – 1.75 
x ULN 
> 1.75 x ULN 
Bilirubin – when Liver Function 
Test is normal; increase by 
factor 
1.1 – 1.5 x 
ULN 
1.6 – 2.0 x 
ULN 
2.0 – 3.0 x 
ULN 
> 3.0 x ULN 
Cholesterol 
201 – 210 
211 – 225 
> 226 
--- 
Pancreatic enzymes – 
amylase, lipase 
1.1 – 1.5 x 
ULN 
1.6 – 2.0 x 
ULN 
2.1 – 5.0 x 
ULN 
> 5.0 x ULN 
* The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal parameters. 
Institutional normal reference ranges should be provided to demonstrate that they are appropriate. 
** The clinical signs or symptoms associated with laboratory abnormalities might result in characterization of the laboratory 
abnormalities as Potentially Life Threatening (Grade 4). For example. a low sodium value that falls within a grade 3 
parameter (125-129 mE/L) should be recorded as a grade 4 hyponatremia event if the subject had a new seizure associated 
with the low sodium value. 
***ULN" is the upper limit of the normal range.  
 
Hematology * 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Hemoglobin (Female) - gm/dL 11.0 – 12.0 9.5 – 10.9 
8.0 – 9.4 
< 8.0 
Hemoglobin (Female) change 
from baseline value - gm/dL 
Any 
decrease – 
1.5 
1.6 – 2.0 
2.1 – 5.0 
> 5.0 
Hemoglobin (Male) - gm/dL 
12.5 – 13.5 10.5 – 12.4 8.5 – 10.4 
< 8.5 
Hemoglobin (Male) change 
from baseline value – gm/dL 
Any 
decrease – 
1.5 
1.6 – 2.0 
2.1 – 5.0 
> 5.0 
WBC Increase - cell/mm3 
10,800 – 
15,000 
15,001 – 
20,000 
20,001 – 25, 
000 
> 25,000 
WBC Decrease - cell/mm3 
2,500 – 
3,500 
1,500 – 
2,499 
1,000 – 
1,499 
< 1,000 
Lymphocytes Decrease - 
cell/mm3 
750 – 1,000 500 – 749 
250 – 499 
< 250 
Neutrophils Decrease - 
cell/mm3 
1,500 – 
2,000 
1,000 – 
1,499 
500 – 999 
< 500 
Eosinophils - cell/mm3 
650 – 1500 1501 - 5000 > 5000 
Hypereosinophilic 

 
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Platelets Decreased - cell/mm3 125,000 – 
140,000 
100,000 – 
124,000 
25,000 – 
99,000 
< 25,000 
PT – increase by factor 
(prothrombin time) 
1.0 – 1.10 x 
ULN** 
ï€ 1.11 – 
1.20 x ULN 
1.21 – 1.25 
x ULN 
> 1.25 ULN 
PTT – increase by factor 
(partial thromboplastin time) 
1.0 – 1.2 x 
ULN 
1.21 – 1.4 x 
ULN 
1.41 – 1.5 x 
ULN 
> 1.5 x ULN 
Fibrinogen increase - mg/dL 
400 – 500 
501 – 600 
> 600 
-- 
Fibrinogen decrease - mg/dL 
150 – 200 
125 – 149 
100 – 124 
< 100 or 
associated with 
gross bleeding or 
disseminated 
intravascular 
coagulation (DIC) 
* The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal parameters. 
Institutional normal reference ranges should be provided to demonstrate that they are appropriate. 
** "ULN" is the upper limit of the normal range.  
 
Urine * 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Protein 
Trace 
1+ 
2+ 
Hospitalization or 
dialysis 
Glucose 
Trace 
1+ 
2+ 
Hospitalization 
forhyperglycemia 
Blood (microscopic) - red blood 
cells per high power field 
(rbc/hpf) 
1 - 10 
11 - 50 
> 50 and/or 
gross blood 
Hospitalization or 
packed red blood 
cells (PRBC) 
transfusion 
* The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal parameters. 
Institutional normal reference ranges should be provided to demonstrate that they are appropriate