68Ga-PSMA-PET/CT Imaging for Locally Advanced, Recurrent and Metastatic Adenoid Cystic Carcinoma or Salivary Duct Carcinoma
Phase: NA
Conditions: Salivary Gland Cancer, Adenoid Cystic Carcinoma, Salivary Duct Carcinoma
Sponsor: Radboud University Medical Center

NL61699.091.17 / PSMA-PET imaging for advanced ACC/SDC 
 
 
 
PROTOCOL TITLE ’68Ga-PSMA-PET/CT imaging for locally advanced, recurrent and 
metastatic adenoid cystic carcinoma or salivary duct carcinoma’ 
Protocol ID 
104902 
Short title 
PSMA-PET imaging for advanced ACC/SDC 
EudraCT number  
2017-002093-40 
Version 
3 
Human Subjects Review 
Approved by CMO Regio Arnhem-Nijmegen, Approval 
Number: 2017-3455 
NCT number 
Not yet available 
Date 
17-08-2017 
Coordinating investigator/project 
leader 
 
Mw. Dr. Carla M.L. van Herpen 
Geert Grooteplein Zuid 8 
Postbus 9101 
6500 HB Nijmegen 
Carla.vanherpen@radboudumc.nl 
Tel: 024 3667251 
Principal investigator(s) (in 
Dutch: hoofdonderzoeker/ 
uitvoerder) 
Mw. Dr. Carla M.L. van Herpen 
 
Sponsor (in Dutch: 
verrichter/opdrachtgever) 
Radboudumc 
Geert Grooteplein Zuid 10 
Postbus 9101 
6500 HB Nijmegen 
Subsidising party 
Adenoid Cystic Carcinoma Research Foundation, 
USA 
Independent expert (s) 
Dr. A.J. Croockewit 
Geert Grooteplein Zuid 8 
Postbus 9101 
6500 HB Nijmegen 
Sandra.Croockewit@radboudumc.nl 
Tel: 024 361 88 00 
Laboratory sites 
Not applicable 
Pharmacy 
Pharmacy Department / Department of Radiology and 
Nuclear Medicine 
Radboudumc 
Geert Grooteplein 10 
6525 GA Nijmegen 
Licence number: 4095 F 

NL61699.091.17 / PSMA-PET imaging for advanced ACC/SDC 
 
 
 
PROTOCOL SIGNATURE SHEET 
 
Name 
Signature 
Date 
Head of Department: 
Prof. Dr. Ir. Koos J.J.M. van der Hoeven 
Geert Grooteplein Zuid 8 
6525 GA Nijmegen 
Koos.vanderhoeven@radboudumc.nl 
Tel: +31-243667251 
 
 
Principal Investigator: 
Mw. Dr. Carla M.L. van Herpen 
Geert Grooteplein Zuid 8 
Postbus 9101 
6525 GA Nijmegen 
Carla.vanherpen@radboudumc.nl  
Tel: +31-243667251 
 
 
 
 

NL61699.091.17 / PSMA-PET imaging for advanced ACC/SDC 
 
 
 
TABLE OF CONTENTS 
1. 
INTRODUCTION AND RATIONALE .............................................................................. 8 
2. 
OBJECTIVES ................................................................................................................11 
3. 
STUDY DESIGN ...........................................................................................................12 
4. 
STUDY POPULATION ..................................................................................................13 
4.1 
Population (base) ...................................................................................................13 
4.2 
Inclusion criteria .....................................................................................................13 
4.3 
Exclusion criteria ....................................................................................................13 
4.4 
Sample size calculation ..........................................................................................14 
5. 
TREATMENT OF SUBJECTS .......................................................................................15 
6. 
INVESTIGATIONAL PRODUCT ....................................................................................16 
6.1 
Name and description of investigational  product(s) ...............................................16 
6.2 
Summary of findings from non-clinical studies ........................................................16 
6.3 
Summary of findings from clinical studies ...............................................................16 
6.4 
Summary of known and potential risks and benefits ...............................................16 
6.5 
Description and justification of route of administration and dosage .........................16 
6.6 
Dosages, dosage modifications and method of administration ...............................16 
6.7 
Preparation and labelling of Investigational Medicinal Product ...............................16 
6.8 
Drug accountability .................................................................................................17 
7. 
NON-INVESTIGATIONAL PRODUCT ...........................................................................18 
8. 
METHODS ....................................................................................................................19 
8.1 
Study parameters/endpoints ...................................................................................19 
8.1.1 
Main study parameter/endpoint .......................................................................19 
8.1.2 
Secondary study parameters/endpoints ..........................................................19 
8.1.3 
Other study parameters ...................................................................................19 
8.2 
Randomisation, blinding and treatment allocation ..................................................19 
8.3 
Study procedures ...................................................................................................19 
8.4 
Withdrawal of individual subjects ............................................................................20 
8.5 
Replacement of individual subjects after withdrawal ...............................................20 
8.6 
Follow-up of subjects withdrawn from treatment .....................................................20 
8.7 
Premature termination of the study .........................................................................21 
9. 
SAFETY REPORTING ..................................................................................................22 
9.1 
Temporary halt for reasons of subject safety ..........................................................22 
9.2 
AEs, SAEs and SUSARs ........................................................................................22 
9.2.1 
Adverse events (AEs) ......................................................................................22 
9.2.2 
Serious adverse events (SAEs) .......................................................................22 
9.2.3 
Suspected unexpected serious adverse reactions (SUSARs) .........................23 
9.3 
Annual safety report ...............................................................................................24 
9.4 
Follow-up of adverse events ...................................................................................24 
9.5 
Data Safety Monitoring Board (DSMB) ...................................................................24 
10. 
STATISTICAL ANALYSIS ..........................................................................................25 
10.1 
Primary study parameter(s) ....................................................................................25 
10.2 
Secondary study parameter(s) ...............................................................................25 

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10.3 
Other study parameters ..........................................................................................25 
10.4 
Interim analysis ......................................................................................................25 
11. 
ETHICAL CONSIDERATIONS ...................................................................................26 
11.1 
Regulation statement .............................................................................................26 
11.2 
Recruitment and consent........................................................................................26 
11.3 
Objection by minors or incapacitated subjects ........................................................26 
11.4 
Benefits and risks assessment, group relatedness .................................................26 
11.5 
Compensation for injury .........................................................................................26 
11.6 
Incentives ...............................................................................................................27 
12. 
ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION .........................28 
12.1 
Handling and storage of data and documents ........................................................28 
12.2 
Monitoring and Quality Assurance ..........................................................................28 
12.3 
Amendments ..........................................................................................................28 
12.4 
Annual progress report ...........................................................................................28 
12.5 
Temporary halt and (prematurely) end of study report ............................................29 
12.6 
Public disclosure and publication policy ..................................................................29 
13. 
STRUCTURED RISK ANALYSIS...............................................................................30 
13.1 
Potential issues of concern .....................................................................................30 
13.2 
Synthesis ...............................................................................................................31 
14. 
REFERENCES ..........................................................................................................32 

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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS  
 
 
11C 
Carbon-11 
18F 
Fluoride-18 
68Ga 
Gallium-68 
177Lu 
Lutetium-177 
ABR 
ABR form, General Assessment and Registration form, is the application form 
that is required for submission to the accredited Ethics Committee (In Dutch, ABR 
= Algemene Beoordeling en Registratie) 
ACC 
Adenoid cystic carcinoma 
ACCRF 
Adenoid Cystic Carcinoma Research Foundation 
AE 
Adverse Event 
ALT 
Alanine transaminase 
AR 
Adverse Reaction 
AST 
Aspartate transaminase 
CCMO 
Central Committee on Research Involving Human Subjects; in Dutch: Centrale 
Commissie Mensgebonden Onderzoek 
CT 
Computed Tomography 
CV 
Curriculum Vitae 
DSMB 
Data Safety Monitoring Board 
EU 
European Union 
FDG 
Fluorodeoxyglucose 
GCP 
Good Clinical Practice 
IB 
Investigator’s Brochure 
IC 
Informed Consent 
IMP 
Investigational Medicinal Product  
IMPD 
Investigational Medicinal Product Dossier  
KWF 
Koningin Wilhelmina Fonds (Dutch Cancer Society) 
MBq 
Megabecquerel 
METC  
Medical research ethics committee (MREC); in Dutch: medisch ethische toetsing 
commissie (METC) 
MRI 
Magnetic resonance imaging 
PD 
Progressive disease 
PET 
Positron emission tomography 
PIF 
Patient information form 
PR 
Partial response 

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PSA 
Prostate specific antigen 
PSMA 
Prostate specific membrane antigen 
(S)AE 
(Serious) Adverse Event  
SD 
Stable disease 
SDC 
Salivary duct carcinoma 
SPC 
Summary of Product Characteristics (in Dutch: officiële productinfomatie IB1-
tekst) 
Sponsor The sponsor is the party that commissions the organisation or performance of the 
research, for example a pharmaceutical company, academic hospital, scientific 
organisation or investigator. A party that provides funding for a study but does not 
commission it is not regarded as the sponsor, but referred to as a subsidising 
party. 
SPSS 
Statistical package for the social sciences 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
SUV 
Standardized uptake value 
ULN 
Upper limit of normal 
Wbp 
Personal Data Protection Act (in Dutch: Wet Bescherming Persoonsgevens) 
WMO 
Medical Research Involving Human Subjects Act (in Dutch: Wet Medisch-
wetenschappelijk Onderzoek met Mensen 

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SUMMARY 
 
Rationale: PSMA is a transmembrane protein, which is expressed on prostate cancers cells, 
ACC and other malignancies. In prostate cancer, distant metastases can be visualized 
sensitively and non-invasively with 68Ga-PSMA-PET/CT scans and if the uptake of 68Ga is 
high enough, patients can be treated with the β-emitting radionuclide 177Lu-PSMA. In the 
current study, we will evaluate the uptake of 68Ga-PSMA by performing 68Ga-PSMA-PET/CT 
scans in advanced ACC and SDC patients. If the uptake is high enough, this will form the 
rationale for a therapeutic study with 177Lu-PSMA in ACC and SDC. 
Objective: The primary objective is to evaluate the uptake of 68Ga-PSMA in locally 
advanced, recurrent and metastatic ACC/SDC by performing 68Ga-PSMA-PET/CT scans. 
The secondary objectives are to calculate the SUV tumor-to-background ratio and tumor-to-
‘healthy salivary gland tissue’ ratio. To correlate the SUV to the degree of 
immunohistochemical PSMA expression of the primary tumor on archival tissue, and to 
establish whether new metastatic lesions are found by 68GA-PSMA-PET/CT imaging. 
Study design: Diagnostic study which evaluates the level of PSMA expression in ACC/SDC 
patients with 68Ga-PSMA-PET/CT imaging in order to establish whether these patients are 
eligible for 177Lu-PSMA therapy. 
Study population: Patients with locally advanced, recurrent or metastatic ACC/SDC of ≥18 
years old. 
Main study parameters/endpoints: the main study endpoints are the tumor SUV, the SUV 
tumor-to-background ratio, the SUV tumor-to-‘healthy salivary gland tissue’ ratio, and the 
correlation between the SUV and the degree of immunohistochemical PSMA expression of 
the primary tumor on archival tissue. 
Nature and extent of the burden and risks associated with participation, benefit and 
group relatedness: Participants will undergo 68Ga-PSMA-PET/CT imaging and a 
venapuncture. These are standard diagnostic procedures with a known minimal safety risk. 
The participant will be asked to make 2 study related visits, which will take 3 hours in total. A 
participant will not benefit from participating in this study. The study does not involve minor or 
incapacitated subjects. 

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1. INTRODUCTION AND RATIONALE 
PSMA is a transmembrane protein. PSMA expression can be visualized and quantified by 
immunohistochemical staining of tissue biopsies with anti-PSMA monoclonal antibodies.1 
This has been done for numerous healthy and malignant tissues. PSMA expression appears 
to be restricted to a few healthy tissues, such as the prostate, duodenum, proximal renal 
tubules, breast and skeletal muscle.2 Results on PSMA expression of healthy salivary gland 
tissue are conflicting.1-4 In malignant tissue, PSMA expression was found in prostate cancer 
cells and the neovasculature of many other solid malignancies, including renal cell 
carcinoma, bladder cancer, colon cancer, neuroendocrine carcinoma, melanoma, pancreatic 
cancer, non-small cell lung cancer, breast cancer and others.2 In ACC, a study in 54 patients 
showed PSMA expression in 85% of patients, and in 70% of patients with recurrent ACC.5 
The level of PSMA expression in SDC is currently under investigation, and the first results 
show PSMA expression in >80% of patients. 
 
PSMA expression is of increasing importance, as it is a target for cancer diagnostics. After 
labelling PSMA ligands with 68Ga, PSMA expression can be visualized non-invasively with a 
68Ga-PSMA-PET/CT scan. In a study in 248 patients with a history of prostate cancer who 
presented with a rising PSA level, it was found that 68Ga-PSMA-PET/CT scans visualized 
substantially more tumor lesions than reported for other imaging modalities, such as CT, 18F-
FDG-PET (figure 1), 11C-choline-PET and MRI.6 This demonstrates that radiolabeled PSMA 
ligands very effectively target prostate cancer lesions in vivo, allowing specific and sensitive 
detection of prostate cancer lesions with PET.  
 
 
Figure 1. 18F-FDG-PET scan (left) and 68Ga-PSMA-PET scan (right) in a patient with metastatic prostate cancer. 
The black dots in the abdomen on the right scan represent prostate cancer metastases that could not be 
visualized by 18F-FDG-PET. 

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Next to its diagnostic importance, the efficient and specific targeting of PSMA paved the road 
to exploring the therapeutic potential of PSMA ligands labeled with β-emitting radionuclides, 
such as 177Lu. We recently showed that 177Lu-PSMA effectively inhibited the growth of PSMA 
expressing tumors in a mouse model for prostate cancer.7 The first results of radionuclide 
therapy studies with 177Lu-PSMA in prostate cancer patients who failed conventional 
therapeutic options have been published recently.8-10 The group in Bad Berka in Germany 
reported the results of the first 56 patients with castration resistant prostate cancer treated 
with 1-4 cycles of 6,000 MBq 177Lu-PSMA. 177Lu-PSMA showed high, specific and rapid 
uptake in prostate cancer metastases, with almost complete retention during 1-2 weeks after 
injection. In these advanced stage patients remarkable therapeutic responses were seen: of 
56 patients, 45 (80.4 %) demonstrated a reduction in PSA levels and 31 patients (56%) had 
a partial response according to EORTC criteria11 (figure 2). 
 
 
Figure 2. Response in castration resistant prostate cancer patients treated with 177Lu-PSMA.8 
 
The group in Munich treated 19 patients with metastatic castration resistant prostate cancer 
with a total of 40 cycles of 7400 MBq of 177Lu-PSMA (1-4 cycles per patient). Only mild side 
effects were seen in part of the patients: dry mouth (37%), anemia (32%) and 
thrombocytopenia (25%). Most importantly, marked PSA responses were seen in most 
patients (44% of patients showed a reduction of ≥50%). Assessment of bone and soft tissue 
metastases showed complete remission in 5% of patients (figure 3), stable disease in 63% 
and progressive disease in 32%. 

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Figure 3. Complete remission in a 71-year-old patient after 4 cycles of 177Lu-PSMA.9  
 
In summary, prostate cancer lesions can be targeted efficiently with radiolabeled PSMA 
ligands. Labeled with 68Ga, PSMA ligands can be used to sensitively detect these tumors 
noninvasively with PET. Labeled with β-emitting radionuclides such as 177Lu, PSMA ligands 
are a new class of powerful therapeutics for targeted radionuclide therapy.  
 
In the current study, we will evaluate the uptake of 68Ga-PSMA by performing 68Ga-PSMA-
PET/CT scans in locally advanced, recurrent and metastatic ACC/SDC patients. Tumor 
uptake will be measured quantitatively. The tumor-to-background ratio and tumor-to-‘healthy 
salivary gland tissue’ ratio will be calculated. Tumor uptake will also be correlated to the 
degree of immunohistochemical PSMA expression of the primary tumor on archival tissue. 
 
This study is of relevance for patients with locally advanced, recurrent or metastatic 
ACC/SDC because treatment options are very limited and 177Lu-PSMA could be a promising 
new treatment option. In prostate cancer, 177Lu-PSMA therapy has proven its value as stated 
above. In ACC/SDC this therapy may also be effective because PSMA expression in 
ACC/SDC is observed immunohistochemically and in a case report on 68Ga-PSMA-PET/CT 
imaging in ACC.12 In order to establish whether ACC/SDC patients are eligible for 177Lu-
PSMA therapy, the level of PSMA expression has to be established with 68Ga-PSMA-PET/CT 
scans. This is the goal of this study. If this study indeed shows sufficient PSMA expression, a 
therapeutic study with 177Lu-PSMA will be started in next future. 
 

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2. OBJECTIVES 
Primary Objective: To evaluate the uptake of 68Ga-PSMA in locally advanced, recurrent and 
metastatic ACC/SDC by performing 68Ga-PSMA-PET/CT scans. 
 
Secondary Objective(s): 
 
To calculate the SUV tumor-to-background ratio and tumor-to-‘healthy salivary gland 
tissue’ ratio. 
 
Correlate the tumor uptake (SUV) to the degree of immunohistochemical PSMA 
expression of the primary tumor on archival tissue. 
 
To establish whether new metastatic lesions are found by 68GA-PSMA-PET/CT 
imaging 
 

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3. STUDY DESIGN 
Design: diagnostic study which evaluates the level of PSMA expression in ACC/SDC patients 
with 68Ga-PSMA-PET/CT imaging in order to establish whether these patients are eligible for 
177Lu-PSMA therapy.c 
Duration: each patients has to make 2 additional visits (apart from normal patient care) when 
he or she participates in this study. These 2 visits will take approximately 3 hours in total. 
Setting: single center study (Radboud university medical center, Nijmegen, the Netherlands) 
 
Telephone consultation or during normal patient care
- Answer questions
- If patients wants to participate: plan screening visit
During normal patient care
- inform eligible patients
- hand out PIF
Study visit
- Perform a 68Ga-PSMA-PET/CT scan
Screening visit
- Review of inclusion and exclusion criteria
- Obtain written IC
- Review of demographic data, medical history, 
allergies, and vital signs
- Asses serum AST, ALT, and creatinine unless done 
within 14 days prior to visit
 
Figure 4. Flow chart of study procedures. 
 

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4. STUDY POPULATION 
4.1 Population (base)  
Study population: Patients with locally advanced, recurrent or metastatic ACC/SDC. 
 
Source population: 
 
Patients with locally advanced, recurrent or metastatic ACC/SDC who are treated at 
the Department of Medical Oncology of the Radboudumc. 
 
Patients with locally advanced, recurrent or metastatic ACC/SDC who heard or read 
about this study and contact the investigators to ask whether they can take part in the 
study. Potential participants will not be actively recruited. However, there will be a 
message on the website of Dutch Salivary Gland Cancer Patient Platform: 
http://speekselklierkanker.org/. This message is added to this submission (see ‘E3 
Wervingsmateriaal’). 
As the Radboudumc is the largest clinic and research center for locally advanced, 
recurrent and metastatic ACC/SDC in the Netherlands, we do not expect problems to 
recruit 15 ACC and 10 SDC patients. 
 
Feasibility analysis 
The Radboud University Medical Center is a tertiary referral center for head and neck 
cancer and salivary gland cancer in particular, receiving referrals from the other academic 
medical centers in the Netherlands. In 2016 40 new advanced SGC patients were seen at 
our outpatient department. In addition, patients who have been under control for longer at 
our OPD may be included directly from the start of the study. Therefore we believe it is 
feasible to enroll 15 ACC patients en 10 SDC patients within the relatively short time 
period of 12 months. 
 
4.2 Inclusion criteria 
In order to be eligible to participate in this study, a subject must meet all of the following 
criteria: 
 
locally advanced, recurrent or metastatic ACC/SDC  
 
Age ≥ 18 years old 
 
Ability to provide written informed consent 
 
4.3 Exclusion criteria 
A potential subject who meets any of the following criteria will be excluded from 
participation in this study: 

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 
Contra-indication for PET imaging 
o Pregnancy 
o Breast feeding 
o Severe claustrophobia 
 
Impaired renal function: MDRD <30 ml/min/1,73 m2 
 
Impaired liver function: AST and ALT ≥ 2.5 x ULN (≥5 x ULN for patients with liver 
metastases) 
 
4.4 Sample size calculation 
The main purpose of this study is to establish the feasibility and value of 68Ga-PSMA-
PET/CT scans as a non-invasive method to assess PSMA expression in ACC/SDC 
patients. An exact sample size calculation is not applicable, because baseline information 
concerning the uptake of 68Ga-PSMA in ACC/SDC patients is not available. Therefore we 
will establish 68Ga-PSMA-PET/CT scanning in 15 ACC and 10 SDC patients. If the 
technique does not prove its value in these patients, we will conclude that it is not a 
valuable imaging technique for ACC/SDC patients. 
 
 
 

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5. TREATMENT OF SUBJECTS 
Not applicable (no intervention study) 

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6. INVESTIGATIONAL PRODUCT  
6.1 Name and description of investigational  product(s) 
PSMA‐HBED –CC consists of a PSMA binding sequence glutamate‐urea‐lysine coupled 
to the chelator HBED‐CC which allows labelling with Ga‐68. More information about the 
investigational product can be found in the IB (chapter 4: Physical, Chemical and 
Pharmaceutical Properties and Formulation, page 8) and the IMPD (chapter 2.1.S: drug 
substance, page 6) 
 
6.2 Summary of findings from non-clinical studies 
See the IB, chapter 5: nonclinical studies, page 11 
 
6.3 Summary of findings from clinical studies 
See the IB, chapter 6: clinical studies, page 13 
 
6.4 Summary of known and potential risks and benefits 
See the IB, chapter 6.2: safety and efficacy, page 15 
 
6.5 Description and justification of route of administration and dosage 
The final formulation of the product is 68Ga- PSMA-HBED-CC in ethanol 7% in PBS (14 
ml), 2MBq / kg / body weight 68Ga, 10 µg PSMA-HBED-CC, which is administered 
intravenously in a single injection. This is in line with previous studies on the 
investigational product for prostate cancers patients. 
 
6.6 Dosages, dosage modifications and method of administration 
Dosage and method of administration are mentioned above. Dosage modifications are not 
applicable as participants get only one dose. 
 
6.7 Preparation and labelling of Investigational Medicinal Product 
Information about the preparation of the investigational product can be found in the IMPD 
(chapter 2.1.S.2: Manufacture, page 8). Information about labelling can also be found in 
the IMPD (chapter 2.1.P.7: ContainerClosureSystem, page 28). 
 

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6.8 Drug accountability 
The investigational product will be produced on site (Department of Radiology and 
Nuclear Medicine, Radboudumc).The investigational product is dispensed in a closed 
20ml sterile glass type 1 vial with a sterile bromobutyl stopper (sealed with an aluminium 
cap), and labeled as depicted on page 28 of the IMPD. These labels of the bulk vial are 
only to be used for internal use in the cleanroom in which the product is dispensed and in 
which aseptic compounding is performed (“Hotlab”). Labeling of the patient dose in the 
syringe complies to annex 13 and is also shown on the same page. After aseptic 
compounding of the patient dose, the remaining solution is stored as retention sample. 

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7. NON-INVESTIGATIONAL PRODUCT 
Not applicable 
 

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8. METHODS 
8.1 Study parameters/endpoints 
8.1.1 Main study parameter/endpoint 
The SUV of 68Ga-PSMA estimated with 68GA-PSMA-PET scanning. If the SUV of 
tumor tissue is higher than the SUV of healthy salivary gland tissue and/or 
comparable to the SUV in prostate cancer, the level of PSMA expression is deemed 
high enough to pursue a therapeutic study with 177Lu-PSMA. 
8.1.2 Secondary study parameters/endpoints 
 
the SUV tumor-to-background ratio 
 
the SUV tumor-to-‘healthy salivary gland tissue’ ratio. 
 
The correlation between the SUV and the degree of immunohistochemical 
PSMA expression of the primary tumor on archival tissue. 
 
The establishment of new metastatic lesions. 
8.1.3 Other study parameters 
 
Birth date 
 
Gender 
 
General medical history 
 
Medication use 
 
Allergies 
 
ACC/SDC history: diagnosis date, location primary tumor, TNM stage at 
diagnosis, ex-PA?, AR-status, HER2-status, type of surgery, date of surgery, 
postoperative radiotherapy, date of radiotherapy, adjuvant systemic therapy, 
location of recurrence, date of recurrence, palliative treatments 
 
Laboratory tests: MDRD, AST, ALT 
 
Pathology: immunohistochemical PSMA expression on archival tissue 
 
 
8.2 Randomisation, blinding and treatment allocation 
Not applicable 
 
8.3 Study procedures 
 
Interview to collect background data 

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o During the screening visit the participants will be asked questions to obtain 
background data, such as birth data, past medical history, current medication 
use and allergies. 
 
Review of electronic patient file 
o Participants will be asked their consent for review of their patient file in order 
to obtain specific background data, such as type of surgery performed and 
date of surgery. 
 
Laboratory tests 
o If not performed within the last 14 days, AST, ALT and creatinine levels will be 
tested. All test will be done by the Clinical Chemical Laboratory of the 
Radboudumc. For this, blood will be taken with a 3 ml lithium-heparin tube 
(light-green cap). The remaining blood will be destroyed after the laboratory 
tests were performed.  
 
68Ga-PSMA-PET/CT imaging 
o The patients will be injected with 68Ga-PSMA with a dose of 2MBq/kg body 
weight and PET/CT scanning (from groin to skull top, 3 minutes per bed 
position, 4-5 bed positions) will be performed 45-60 minutes post injection. 
 
Pathology: PSMA staining 
o On archival tissue, PSMA expression will be evaluated 
immunohistochemically in order to correlate immunhistochemical PSMA 
expression to the SUV. 
 
8.4 Withdrawal of individual subjects 
Subjects can leave the study at any time for any reason if they wish to do so without any 
consequences. The investigator can decide to withdraw a subject from the study for 
urgent medical reasons. 
 
8.5 Replacement of individual subjects after withdrawal 
If a subject decides to withdraw, another patient will be recruited until 15 ACC and 10 
SDC patients have completed the study protocol. 
 
8.6 Follow-up of subjects withdrawn from treatment 
Subjects who decide to withdraw, will not get study related follow-up. 
 

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8.7 Premature termination of the study 
As 68Ga-PSMA-PET/CT imaging is a imaging modality often used in prostate cancer, we 
do not except unforeseen side effect of this imaging modality. If unexpected side effect do 
appear in this patient group, termination of the study will be considered, depending on the 
seriousness and frequency.  
  
 
 

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9. SAFETY REPORTING 
9.1 Temporary halt for reasons of subject safety 
In accordance to section 10, subsection 4, of the WMO, the sponsor will suspend the 
study if there is sufficient ground that continuation of the study will jeopardise subject 
health or safety.  The sponsor will notify the accredited METC without undue delay of a 
temporary halt including the reason for such an action. The study will be suspended 
pending a further positive decision by the accredited METC. The investigator will take 
care that all subjects are kept informed.  
 
9.2 AEs, SAEs and SUSARs 
9.2.1 Adverse events (AEs) 
Adverse events are defined as any undesirable experience occurring to a subject 
during the study, whether or not considered related to the trial procedure. All 
adverse events reported spontaneously by the subject or observed by the 
investigator or his staff will be recorded. 
 
9.2.2 Serious adverse events (SAEs) 
A serious adverse event is any untoward medical occurrence or effect that  
- 
results in death; 
- 
is life threatening (at the time of the event); 
- 
requires hospitalisation or prolongation of existing inpatients’ hospitalisation; 
- 
results in persistent or significant disability or incapacity; 
- 
is a congenital anomaly or birth defect; or 
- 
any other important medical event that did not result in any of the outcomes listed 
above due to medical or surgical intervention but could have been based upon 
appropriate judgement by the investigator. 
An elective hospital admission will not be considered as a serious adverse event. 
 
The investigator will report all SAEs to the sponsor without undue delay after 
obtaining knowledge of the events.    . 
 
The sponsor will report the SAEs through the web portal ToetsingOnline to the 
accredited METC that approved the protocol, within 7 days of first knowledge for 
SAEs that result in death or are life threatening followed by a period of maximum of 8 

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days to complete the initial preliminary report. All other SAEs will be reported within a 
period of maximum 15 days after the sponsor has first knowledge of the serious 
adverse events. 
9.2.3 Suspected unexpected serious adverse reactions (SUSARs) 
Adverse reactions are all untoward and unintended responses to an investigational 
product related to any dose administered. 
 
Unexpected adverse reactions are SUSARs if the following three conditions are met: 
1. the event must be serious (see chapter 9.2.2); 
2. there must be a certain degree of probability that the event is a harmful and an 
undesirable reaction to the medicinal product under investigation, regardless of 
the administered dose; 
3. the adverse reaction must be unexpected, that is to say, the nature and severity 
of the adverse reaction are not in agreement with the product information as 
recorded in the Investigator’s Brochure. 
 
The sponsor will report expedited the following SUSARs through the web portal 
ToetsingOnline  to the METC: 
 SUSARs that have arisen in the clinical trial that was assessed by the METC; 
 SUSARs that have arisen in other clinical trials of the same sponsor and with the 
same medicinal product, and that could have consequences for the safety of the 
subjects involved in the clinical trial that was assessed by the METC. 
The remaining SUSARs are recorded in an overview list (line-listing) that will be 
submitted once every half year to the METC. This line-listing provides an overview 
of all SUSARs from the study medicine, accompanied by a brief report highlighting 
the main points of concern.  
The expedited reporting of SUSARs through the web portal Eudravigilance or 
ToetsingOnline is sufficient as notification to the competent authority. 
 
The sponsor will report expedited all SUSARs to the competent authorities in other 
Member States, according to the requirements of the Member States.  
 
The expedited reporting will occur not later than 15 days after the sponsor has first 
knowledge of the adverse reactions. For fatal or life threatening cases the term will 
be maximal 7 days for a preliminary report with another 8 days for completion of the 
report.  

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9.3 Annual safety report 
In addition to the expedited reporting of SUSARs, the sponsor will submit, once a year 
throughout the clinical trial, a safety report to the accredited METC, competent authority, 
and competent authorities of the concerned Member States. 
This safety report consists of: 
 a list of all suspected (unexpected or expected) serious adverse reactions, along with 
an aggregated summary table of all reported serious adverse reactions, ordered by 
organ system, per study; 
 a report concerning the safety of the subjects, consisting of a complete safety analysis 
and an evaluation of the balance between the efficacy and the harmfulness of the 
medicine under investigation. 
 
9.4 Follow-up of adverse events 
All AEs will be followed until they have abated, or until a stable situation has been 
reached. Depending on the event, follow up may require additional tests or medical 
procedures as indicated, and/or referral to the general physician or a medical specialist. 
SAEs need to be reported till end of study within the Netherlands, as defined in the 
protocol  
 
9.5 Data Safety Monitoring Board (DSMB) 
A DSMB is deemed unnecessary because patients are exposed to a known diagnostic 
procedure with a low risk profile.  

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10. STATISTICAL ANALYSIS 
10.1 Primary study parameter(s) 
SUV will be calculated according to the following formula:  
(measured activity concentration [MBq/mL] * body weight [g]) / injected activity [MBq] 
 
The PET/CT images will be reconstructed in three dimensions. The PET and CT images 
will be fused and the SUVs will be aligned with CT to assess 68Ga-PSMA uptake in tumor 
lesions, healthy salivary gland tissue, and the background. 
  
10.2 Secondary study parameter(s)  
Tumor-to-background ratios and tumor-to-‘healthy salivary gland tissue’ ratios will be 
calculated using the SUV. It will be presented as mean and standard deviations. 
 
Immunohistochemical PSMA expression on a tissue sample of the primary tumor will be 
quantified using a four point scale for tumor PSMA expression (0 = no expression, 1 = 
weak expression, 2 = moderate expression, and 3 = strong expression) and the number of 
PSMA-positive blood vessels per mm2 will be counted. 
 
The correlation between the immunohistochemical PSMA expression and tumor SUV will 
be evaluated using linear regression analysis. A p-value of <0.05 will be considered 
significant. Analyses will be performed using SPSS version 22.0. 
 
10.3 Other study parameters 
Background variable will be described using simple desricptive statistics and will be 
presented in a table. Missing data will be mentioned in the final manuscript. 
 
10.4 Interim analysis 
Not applicable 

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11. ETHICAL CONSIDERATIONS 
11.1 Regulation statement 
The study will be conducted according to the principles of the Declaration of Helsinki 
(version 8, 19 October 2013), in accordance with the Medical Research Involving Human 
Subjects Act (WMO), the personal data protection act (Wet Bescherming 
Persoonsgegevens), and the Medical Treatment Agreement Act (WGBO). 
 
11.2 Recruitment and consent 
Patients will be informed about the study by their treating physician during normal patient 
care. Detailed information about the study can be offered by the investigators during 
normal patient care or by phone call. If a patient decides to participate, a screening visit 
will be planned, which starts with signing the IC. At least 24 hours will be taken into 
account between informing patients about the study and signing the IC. 
 
11.3 Objection by minors or incapacitated subjects 
Not applicable 
 
11.4 Benefits and risks assessment, group relatedness 
Risk assessment: as 68Ga-PSMA-PET/CT imaging is a known diagnostic procedure used 
for prostate cancer in normal patient care, the risks of this procedure are well known and 
minimal. Next to this, 30 ml blood will be drawn from the participants by a venapuncture. 
This risks of this procedure are also well known and minimal.  
Benefit assessment: participants will not benefit directly from this study as it is a non-
therapeutic trial. If the study is successful, participants may participate in a therapeutic 
study with 177Lu-PSMA which may be beneficial.  
Group relatedness: the study does not involve minors and/or incapacitated subjects 
 
11.5 Compensation for injury 
The sponsor/investigator has a liability insurance which is in accordance with article 7 of 
the WMO. 
  
The sponsor also has an insurance which is in accordance with the legal requirements in 
the Netherlands (Article 7 WMO). This insurance provides cover for damage to research 
subjects through injury or death caused by the study. 

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The insurance applies to the damage that becomes apparent during the study or within 4 
years after the end of the study. 
 
11.6 Incentives 
Travel expenses and parking costs will be paid. 

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12. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
12.1 Handling and storage of data and documents 
Participants will get a unique research code to anonimize data. The identification code list 
will be secured with a password. The source data will be noted on a eCRF. The eCRF 
data will be noted in a secured database (Castor). Once the study is finished, the 
database will be locked. Data will be stored for 15 years after the end of the study. 
Handling of data is in accordance to the Dutch Personal Data Protection Act (WBP). 
 
12.2 Monitoring and Quality Assurance  
A DSMB is deemed unnecessary because patients are exposed to a known diagnostic 
procedure with a low risk profile. Data will be monitored for accuracy by the investigators. 
For this, univariate checks (empty fields, outlayers), multivariate checks (logical order of 
dates) and visual checks will be used.  
 
12.3 Amendments  
A ‘substantial amendment’ is defined as an amendment to the terms of the METC 
application, or to the protocol or any other supporting documentation, that is likely to 
affect to a significant degree: 
- the safety or physical or mental integrity of the subjects of the trial; 
- the scientific value of the trial; 
- the conduct or management of the trial; or 
- the quality or safety of any intervention used in the trial. 
 
All substantial amendments will be notified to the METC and to the competent authority. 
 
Non-substantial amendments will not be notified to the accredited METC and the 
competent authority, but will be recorded and filed by the sponsor.  
 
12.4 Annual progress report 
The sponsor/investigator will submit a summary of the progress of the trial to the 
accredited METC once a year. Information will be provided on the date of inclusion of the 
first subject, numbers of subjects included and numbers of subjects that have completed 
the trial, serious adverse events/ serious adverse reactions, other problems, and 
amendments.  
 

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12.5 Temporary halt and (prematurely) end of study report 
The sponsor will notify the accredited METC and the competent authority of the end of 
the study within a period of 90 days. The end of the study is defined as the last patient’s 
last visit.  
 
The sponsor will notify the METC immediately of a temporary halt of the study, including 
the reason of such an action. 
 
In case the study is ended prematurely, the sponsor will notify the accredited METC and 
the competent authority within 15 days, including the reasons for the premature 
termination. 
 
 Within one year after the end of the study, the investigator/sponsor will submit a final 
study report with the results of the study, including any publications/abstracts of the study, 
to the accredited METC and the Competent Authority.  
 
12.6 Public disclosure and publication policy 
We aim to submit the study results in a major peer-reviewed oncology journal, i.e., Annals 
of Oncology, Journal of Clinical Oncology within 6 months after the final study procedure. 

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13. STRUCTURED RISK ANALYSIS  
13.1 Potential issues of concern 
a. Level of knowledge about mechanism of action 
68Ga-PSMA-PET imaging is a specific and sensitive method to target prostate cancer 
lesions in vivo.6 In this study we will investigate its value in patients with salivary gland 
cancer, i.e. adenoid cystic carcinoma and salivary duct carcinoma. There are several 
reasons why this could be a valuable imaging modality for these patients. First of all, 
immunohistochemical PSMA-staining show that most ACC and SDC tumor are PSMA-
positive. Second, 68Ga-PSMA-PET scans in prostate cancer patients show uptake of 
68Ga-PSMA in the salivary glands. Third, a case report has proved the principle of 68Ga-
PSMA-PET imaging in a patient with ACC.12 
 
b. Previous exposure of human beings with the test product(s) and/or products with a 
similar biological mechanism 
68Ga-PSMA-PET imaging is an imaging modality which is increasingly being used in 
recurrent prostate cancer patients.13 Because of the wide experience with this imaging 
modality in prostate cancer patients, the safety is well known, and serious adverse events 
have never occurred (see also chapter 6.2 in the IB). 
 
c. Can the primary or secondary mechanism be induced in animals and/or in ex-vivo 
human cell material? 
In preclinical studies, excellent PSMA‐specific tumor imaging in vivo with high tumor 
uptake (3.29 ± 0.77% ID/g) as well as high tumor‐to‐blood (22:1) and tumor‐to‐muscle 
(122:1 at 120 min p.i.) ratios at 120 min p.i. has been described for the PSMA+  tumors. 
Next to this, high specific uptake in PSMA+ murine tissues (among others the salivary 
glands) is observed. More information can be found in the IB (chapter 5: nonclinical 
studies, page 11). 
 
d. Selectivity of the mechanism to target tissue in animals and/or human beings 
PSMA specific imaging is found in animals (see answer to previous question) as well as in 
prostate cancer patients (IB, chapter 6: clinical studies, page 13). 
 
e. Analysis of potential effect 
The safety window is wide, as no serious adverse events have been reported in the 
literature. See the IB (chapter 6.2 and 7, page 15) for more information.  
 

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f. Pharmacokinetic considerations 
See the IB, chapter 6.1: Pharmacokinetics and Product Metabolism in Humans, page 13) 
 
g. Study population 
Patients with locally advanced, recurrent or metastatic ACC or SDC. 
 
h. Interaction with other products 
Not applicable 
 
 
i. Predictability of effect 
In ACC and SDC, the investigational product has not been evaluated before and is 
therefore not yet predictable. In this study we will correlate the SUV of the primary tumor 
with the level of immunohistochemical PSMA staining on archival tissue to establish 
whether the efficacy of PSMA-PET imaging can be predicted with immunohistochemistry. 
 
j. Can effects be managed? 
No side effects which require to be managed have been reported in the literature. 
However, if a participants develops unexpected side-effects, the study center 
(Radboudumc) can deliver adequate medical support of emergencies. 
 
13.2 Synthesis 
In conclusion, 68Ga-PSMA-PET/CT imaging is a imaging modality which is well known 
and often used in patients with recurrent prostate cancer. In these patients, no serious 
side effect have been reported. There is no reason to expect otherwise in our study 
population of patients with incurable ACC or SDC. In case unexpected side-effect do 
occur, the facilities to deliver emergency medical support are available at the study center. 
Therefore, we conclude that the risk of injury is small and if an injury occurs, it will be 
minor, which means the risk classification is negligible according to the NFU-risk 
classification. 
 
 
 
 
 

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