PD-L1 PET Imaging in Patients With an Inoperable Melanoma With Brain Metastasis and Eligible for Treatment With Nivolumab.
Phase: NA
Conditions: Melanoma
Sponsor: University Medical Center Groningen

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PD-L1 PET imaging in patients with melanoma or 
NSCLC with brain metastasis and eligible for 
treatment with nivolumab. 
 
 

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PROTOCOL TITLE: PD-L1 PET imaging in patients with melanoma or NSCLC with brain metastasis 
and eligible for treatment with nivolumab. 
Protocol ID 
2016255-8UU 
Short title 
PD-L1 PET imaging in brainmets 
EudraCT number  
2016-002308-22 
Version 
3.0  
Date 
 20-11-2018 
Coordinating investigator/project 
leader 
 
Prof. Dr. G.A.P. Hospers 
Department of Medical Oncology, UMCG 
Phone number: +31 503612821 
Email: g.a.p.hospers@umcg.nl 
 
Prof.dr. T.J.N. Hiltermann 
Department of Pulmonary Diseases 
Phone number: +31 503616161 
Email:t.j.n.hiltermann@umcg.nl 
Principal investigator(s) (in Dutch: 
hoofdonderzoeker/ uitvoerder) 
 
 
Prof. Dr. G.A.P. Hospers 
Department of Medical Oncology, UMCG 
Phone number: +31 503612821 
Email: g.a.p.hospers@umcg.nl 
 
 
Sponsor (in Dutch: 
verrichter/opdrachtgever) 
University Medical Center Groningen 
Hanzeplein 1 
9713 GZ Groningen 
The Netherlands 
 
 
Subsidising party 
Bristol-Myers Squibb B.V.                                                               

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Orteliuslaan 1000                                                                             
3528 BD Utrecht 
 
Independent expert (s) 
Prof.dr. H.J.M. Groen 
Department of Lung Diseases, UMCG 
Phone number +31 503611546 
Email: h.j.m.groen@umcg.nl 

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PROTOCOL SIGNATURE SHEET 
 
Name 
Signature 
Date 
Sponsor or legal representative: 
Head of Department: 
Prof.dr. J.A. Gietema 
 
 
 
Principal Investigator: 
Prof.dr. G.A.P. Hospers 
 
 
 
 
 

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TABLE OF CONTENTS 
1. 
SUMMARY ....................................................................................................................... 9 
2. 
INTRODUCTION AND RATIONALE .......................................................................................11 
2.1 
Immune checkpoint inhibition ....................................................................................11 
2.2 
PD1/PD-L1 blockade in melanoma and non-small cell lung cancer ..................................11 
2.3 
Molecular imaging with [18F]PD-L1 ............................................................................12 
2.4 
Rationale .................................................................................................................13 
3. 
OBJECTIVES .....................................................................................................................13 
3.1 
Phase one ................................................................................................................13 
3.2 
Phase two ................................................................................................................13 
4. 
STUDY DESIGN .................................................................................................................14 
5. 
STUDY POPULATION.........................................................................................................14 
5.1 
Study population ......................................................................................................14 
5.2 
Inclusion criteria .......................................................................................................15 
5.3 
Exclusion criteria ......................................................................................................16 
5.4 
Sample size calculation ..............................................................................................17 
6. 
TREATMENT OF SUBJECTS.................................................................................................17 
6.1 
Investigational product/treatment ..............................................................................17 
6.2 
Use of co-intervention ...............................................................................................17 
7. 
INVESTIGATIONAL PRODUCT .............................................................................................18 
8. 
NON-INVESTIGATIONAL PRODUCT .....................................................................................19 
8.1 
Name and description of non-investigational product(s) ...............................................19 
8.2 
Summary of findings from non-clinical studies .............................................................19 
8.3 
Summary of findings from clinical studies ....................................................................19 
8.4 
Summary of known and potential risks and benefits .....................................................19 
8.5 
Description and justification of route of administration and dosage ...............................19 
8.6 
Dosages, dosage modifications and method of administration .......................................19 
8.7 
Preparation and labelling of Non Investigational Medicinal Product ...............................19 
8.8 
Drug accountability ...................................................................................................19 
9. 
METHODS .......................................................................................................................20 
9.1 
Primary study parameter/endpoint ............................................................................20 
9.2 
Secondary study parameters/endpoints ......................................................................20 
9.3 
Randomisation, blinding and treatment allocation........................................................20 
9.4 
Study procedures ......................................................................................................20 
9.4.1 
Patient evaluation .............................................................................................20 
9.4.2 
PET procedure and quantification of tracer uptake ................................................21 
9.4.3 
CT scan .............................................................................................................23 
9.4.4 
MRI scan ...........................................................................................................23 
9.4.5 
Biopsy ..............................................................................................................23 
9.4.6 
Immunohistochemistry ......................................................................................23 
9.5 
Withdrawal of individual subjects ...............................................................................24 
9.6 
Replacement of individual subjects after withdrawal ....................................................24 
9.7 
Premature termination of the study ............................................................................24 

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10. 
SAFETY REPORTING ......................................................................................................25 
10.1 
Section 10 WMO event ..............................................................................................25 
10.2 
AEs, SAEs and SUSARs ...............................................................................................25 
10.2.1 
Adverse events (AEs) ..........................................................................................25 
10.2.2 
Nonserious adverse events .................................................................................25 
10.2.3 
Serious adverse events (SAEs) .............................................................................25 
10.2.4 
Suspected unexpected serious adverse reactions (SUSARs) ....................................27 
10.3 
Annual safety report .................................................................................................29 
10.4 
Follow-up of adverse events ......................................................................................29 
11. 
STATISTICAL ANALYSIS ..................................................................................................30 
11.1 
Primary study parameter(s) .......................................................................................30 
11.2 
Secondary study parameter(s) ....................................................................................30 
12. 
ETHICAL CONSIDERATIONS ............................................................................................32 
12.1 
Regulation statement ................................................................................................32 
12.2 
Recruitment and consent...........................................................................................32 
12.3 
Objection by minors or incapacitated subjects (if applicable) .........................................32 
12.4 
Benefits and risks assessment, group relatedness .........................................................32 
12.5 
Compensation for injury ............................................................................................33 
12.6 
Incentives (if applicable) ............................................................................................33 
13. 
ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION ...........................................34 
13.1 
Handling and storage of data and documents ..............................................................34 
13.2 
Monitoring and Quality Assurance ..............................................................................34 
13.3 
Amendments ...........................................................................................................35 
13.4 
Annual progress report ..............................................................................................35 
13.5 
End of study report ...................................................................................................35 
13.6 
Public disclosure and publication policy .......................................................................35 
14. 
STRUCTURED RISK ANALYSIS ..........................................................................................36 
14.1 
Potential issues of concern ........................................................................................36 
14.1.1 
Level of knowledge about mechanism of action ....................................................36 
14.1.2 
Previous exposure of human beings with the test product(s) and/or products with a 
similar biological mechanism .............................................................................................36 
14.1.3 
Can the primary or secondary mechanism be induced in animals and/or in ex-vivo 
human cell material? ........................................................................................................36 
14.1.4 
Selectivity of the mechanism to target tissue in animals and/or human beings .........36 
14.1.5 
Analysis of potential effect .................................................................................36 
14.1.6 
Pharmacokinetic considerations ..........................................................................37 
14.1.7 
Study population ...............................................................................................37 
14.1.8 
Interaction with other products ...........................................................................37 
14.1.9 
Predictability of effect ........................................................................................37 
14.2 
Synthesis .................................................................................................................37 
15. 
REFERENCES ................................................................................................................38 

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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS  
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) 
AE 
Adverse Event 
AR 
Adverse Reaction 
CA 
Competent Authority 
CCMO 
Central Committee on Research Involving Human Subjects; in Dutch: Centrale 
Commissie Mensgebonden Onderzoek 
CTLA-4 
Cytotoxic T-Lymphocyte-associated protein-4 
CV 
Curriculum Vitae 
DSMB 
Data Safety Monitoring Board 
EU 
European Union 
EudraCT European drug regulatory affairs Clinical Trials  
FFPE 
Formalin fixed-paraffin embedded 
GCP 
Good Clinical Practice 
IB 
Investigator’s Brochure 
IC 
IHC 
Informed Consent 
Immunohistochemistry 
IMP 
Investigational Medicinal Product  
IMPD 
Investigational Medicinal Product Dossier  
METC  
 
PD-1 
PD-L1 
PK 
ROI 
Medical research ethics committee (MREC); in Dutch: medisch ethische toetsing 
commissie (METC) 
Programmed Death Receptor-1 
Programmed Death Ligand 1 
Pharmacokinetic 
Region-of-interest 
(S)AE 
(Serious) Adverse Event  
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. 

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SUSAR 
Suspected Unexpected Serious Adverse Reaction 
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 
WOCBP 
Women of child bearing potential 
 
 

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1. SUMMARY 
 
Rationale: Clinical trials have shown efficacy of PD1/PD-L1 checkpoint inhibitors in multiple solid 
tumors, including melanoma. Whole body information with regard to target presence, drug kinetics 
and dynamics, as well as binding of PD-L1 targeting  agents to the immune system cells is lacking. 
Molecular imaging of PD-L1 could lead to new insights on heterogeneity of PD-L1 expression in 
metastatic lesions and be of help in the prediction of response to PD1/PD-L1 inhibitors in a non-
invasive manner.  
Primary objectives: 
Phase one: To assess the dynamics and kinetics of [18F]PD-L1 in human subjects to establish optimal 
scan schedule. 
Phase two: To validate the [18F]PD-L1 PET tracer by association of PD-L1 tumor expression as 
determined on PET and PD-L1 expression as determined by immunohistochemistry and to assess the 
association between the radiological response to anti-PD1 treatment and PD-L1 expression as 
measured by PET scanning and by immunohistochemistry 
Secondary objectives: To determine between-subject and within-subject variability in [18F]PD-L1 
uptake in melanoma and non-small cell lung cancer metastases 
Study design: This is a feasibility study for the use of [18F]PD-L1 as a PET tracer that will be 
conducted in a single center. The study consists of two phases. The aim of phase one is to provide 
pharmacokinetic information on the tracer and to determine the optimal time point for imaging. In 
the second phase the main study objective will be assessed.  
Study population: The study population consists of patients diagnosed with metastatic melanoma or 
non-small cell lung cancer that are eligible for treatment with nivolumab, a PD-1 blocking monoclonal 
antibody. Patients must be at least 18 years of age. In total, a maximum of 15 patients will be 
included.  
Intervention (if applicable): The main intervention of this study is a [18F]PD-L1 PET scan. In both 
phase one and phase two a scan sequence will be performed both at baseline and 6 weeks  after 
initiation of nivolumab treatment. The PET scans will be combined with either a low dose or 
diagnostic CT scan of chest, abdomen and pelvis and a MRI of the brain. In phase two, a biopsy of at 
least 
one 
accessible 
lesion 
will 
be 
performed 
to 
analyze 
PD-L1 
expression 
using 
immunohistochemical staining after each PET scan. 
 Main study parameters/endpoints:  
 
Phase one: To determine the optimal schedule for performing [18F]PD-L1 PET scans. 

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 
Phase two: To assess the association of PD-L1 expression as measured by PD-L1 tracer uptake 
on PET with PD-L1 expression as measured by immunohistochemical (IHC) staining for PD-L1 
of corresponding tumor lesions. 
Nature and extent of the burden and risks associated with participation, benefit and group 
relatedness: The expected applied injected activity of [18F]PD-L1 is 200 MBq, as is the case for most 
other 18F-labeled tracers. The radiation burden for a dose of 200 MBq is approximately 4.4 mSv.  
Patients will receive 2 serial PET scans each accompanied by a low dose CT scan which adds up to a 
total dose of 11.8 mSv. The radiation burden of these patients complies with category III (moderate 
risk) according to the International Commission on Radiological Protection (ICRP) guidelines (ICRP 
publication 62).  
The biopsies needed in phase two of this study are obtained using an invasive procedure. Although 
biopsies are generally considered to be safe, they can be painful and carry certain risks, such as 
bleeding at the puncture site. Biopsies will preferably been taken from easily accessible lesions to 
minimize the burden and risk for the patient. 
Whenever possible, all procedures that are part of the study protocol will be planned during regular 
visits to the hospital as part of care as usual. 
 

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2. INTRODUCTION AND RATIONALE 
Melanoma is the most aggressive form of skin cancer. Its incidence has grown fast over the past few 
decades, with a current worldwide incidence rate of 121.000 and a mortality rate of 31.000 per year 
(1). In recent years important advancements have been made in the treatment of metastatic 
melanoma. One of these was the discovery that cancer could escape immune surveillance by 
expression of inhibitory immune checkpoint molecules, such as CTLA-4 and PD-1/PD-L1.  
Lung cancer is the leading cause of cancer mortality worldwide for both men and women. The main 
risk factor for the development of NSCLC is smoking. In 2012 about 800 patients died of melanoma 
and over 10,000 people died of lung cancer in the Netherlands (2). During the last few years, 
important advancements have been made in the treatment of locally advanced and metastatic 
melanoma and NSCLC. One of them is the discovery and use of immune checkpoint inhibitors as 
successful therapy in these patients.  
 
2.1 Immune checkpoint inhibition 
For T cell activation two signals are necessary: binding of the antigen (AG) presented by the major 
histocompatibility complex to the T-cell receptor (TCR), and costimulatory signals from antigen-
presenting cells (APCs) (3). Whereas co-stimulatory pathways will enhance T cell activation, 
proliferation and differentiation, so called co-inhibitory signaling pathways, such as the PD-1/PD-L1 
axis, will counteract these effects (3,4). Upregulation of these so called checkpoint molecules 
promote attenuation of T cell activation (3). Under normal physiological circumstances, these 
mechanisms regulate tolerance by suppressing the immune response and thus protecting the body 
against self-reactive T cells and controlling inflammation within target organs. Tumors take 
advantage of these and other mechanisms to evade host immune responses and silence the immune 
system.(3,4-8) To overcome the functional unresponsiveness of the immune system and 
subsequently induce tumor regression, checkpoint inhibitors targeting CTLA-4, and more recently 
inhibitors targeting PD1/PD-L1, have been developed and successfully been tested in several solid 
tumor types with durable responses in a subset of patients (3). 
 
2.2 PD1/PD-L1 blockade in melanoma and non-small cell lung cancer 
Current first line therapy for patients with unresectable melanoma consists of treatment with anti-
PD-1 immuneglobulines such as nivolumab (BMS-936558) or pembrolizumab (MK-3475). Both agents 
have shown an increase in overall survival in phase III studies, with preferable toxicity profiles as 
compared to other agents, such as the CTLA-4 inhibitor ipilimumab.  
  

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Data from the phase 1 trial for pembrolizumab showed a confirmed response rate in 38% of the 
patients (9). Objective response rate in a phase 2 trial of nivolumab was 32% (10). Nivolumab led to 
an even more durable response in patients with stage IV melanoma than ipilimumab, with a median 
overall survival of almost 17 months compared to 10 months with ipilimumab. In addition, the safety 
profile of nivolumab is better than that of ipilimumab, with fewer grade 3 or 4 adverse events.  
Because of their different mode of action and different phase of T cell activation in which they play a 
role, combining nivolumab and ipilimumab has been explored in a clinical trial. This combination of 
CTLA-4 and PD1 blockade led to even higher objective response rates of up to 53%. Recently, this 
combination therapy has been approved in the Netherlands for the treatment in unresectable 
melanoma patients. However, the increase in response rates comes at the cost of more toxicity than 
either single agent (11). 
Although efficacy data on immune checkpoint inhibitors are very promising, not all patients will 
benefit from these agents. Also, immune-related adverse events (irAEs), especially in combination 
therapy, can limit the use of immune modulating drugs. Key issues in the future of immunotherapy 
are the understanding of drug kinetics and dynamics in vivo, as well as the effects of these agents on 
the immune system, since these may be of help in the selection of patients that will benefit from 
checkpoint inhibiting therapy.  
The objective response (ORR) rate of anti-PD-1 therapy in NSCLC varies based on histological subtype 
and PD-L1 expression of the tumor. For squamous cell and planocellular carcinoma with low PD-L1 
expression ORR are 17% and 9% respectively (12,13). For low-PD-L1 adenocarcinoma, ORR is 8%. 
High PD-L1 expressing tumours show ORR rates of 30 to 45% (14, 15, 16). 
between 19.4 – 42.5%, depending on PD-L1 expression (17). Compared to docetaxel, anti-PD-1 
therapy showed prolonged survival (10.4 to 12.7 months vs. 8.5 months) (18). Overall, the treatment 
is well tolerated, with 9,5% adverse events of grade 3 or higher (17).Anti-PD-1 therapy was approved 
by the FDA for second line treatment of patients with high PD-L1 expressing NSCLC (>50 % based on 
IHC assay)  in 2015 (16). Recently the indication was expanded to patients with tumors that express 
>=1% PD-L1 (18).  
2.3 Molecular imaging with [18F]PD-L1 
PD-L1 tumor surface expression, which is positive in 40-100% in metastatic melanoma, has been 
studied intensively as a potential biomarker for the selection of patients that qualify for anti-PD-1 
therapy, but not without any obstacles. In early clinical trials, PD-L1 expression has been associated 
with response to PD1/PD-L1 inhibition (19-21). Later trials reported a response to PD1/PD-L1 
checkpoint inhibitors in up to 47% of PD-L1-negative melanomas (22). Also, the potentially 
heterogeneous expression and fast dynamics of PD-L1 expression make clinical implementation 

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difficult (19). By labeling of a PD-L1 binding precursor with Fluoride-18 (18F), serial [18F]PD-L1-PET 
scanning can be used to assess whole body distribution, pharmacokinetics (PK) and 
pharmacodynamics (PD) and to relate findings to treatment effects. This could help in patient 
selection and possibly serve as an (early) biomarker for response to PD1/PD-L1 checkpoint inhibitors 
in the future. 
In NSCLC PD-L1 expression is associated with response to therapy, as illustrated above. Therefore, 
identification of tumors with high PD-L1 expression in this patient category can be of high clinical 
value. 
 
2.4 Rationale  
Clinical trials have shown efficacy of PD1/PD-L1 checkpoint inhibitors in multiple solid tumors, 
including melanoma and NSCLC. Whole body information with regard to target presence, drug 
kinetics and dynamics, as well as binding of PD-L1 targeting agents to the immune system cells is 
lacking. Molecular imaging of PD-L1 could lead to new insights on heterogeneity of PD-L1 expression 
in metastatic lesions and be of help in the prediction of response to PD1/PD-L1 inhibitors in a non-
invasive manner.  
 
3. OBJECTIVES 
3.1 Phase one 
Primary Objective:  
 
To determine the optimal timing of imaging for [18F]PD-L1 tracer imaging of inoperable 
melanoma and NSCLC. 
 
3.2 Phase two 
Primary Objective:  
 
To assess the association of PD-L1 expression as measured by PD-L1 tracer uptake on PET 
and PD-L1 expression as measured by immunohistochemical (IHC) staining for PD-L1 of 
corresponding tumor lesions. 
 
To correlate response to anti-PD1 treatment with differences in tumor PD-L1 and PD1 
expression between baseline and after 6 weeks of treatment, as quantified by PET and IHC 
analysis. 
 
 

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Secondary objectives: 
 
To characterize between-subject and within-subject variability in accumulation of the 
[18F]PD-L1 tracer in melanoma and NSCLC metastases.  
 
4. STUDY DESIGN 
This is a single center feasibility study for the application of [18F]PD-L1 PET in patients with metastatic 
melanoma and NSCLC treated with anti-PD-1 therapy. The study will consist of a pharmacokinetics 
phase (phase one) and tracer validation phase (phase two). Phase one will be performed in a 
maximum of 5 patients. A [18F]PD-L1 PET scan will be performed at baseline and six weeks after 
treatment initiation. Upon finishing phase one, the optimal time for tracer injection will be 
determined prior to the start of phase two. In phase two a [18F]PD-L1 PET-CT scan will be performed 
in 10 patients at baseline and six weeks after treatment initiation. Also, a biopsy will be taken from at 
least one accessible tumor location after the PET-scan at baseline and the PET-scan after six weeks of 
therapy. 
 
 
Fig.1 – General study overview. 
 
5. STUDY POPULATION 
5.1 Study population 
All patients should be diagnosed with stage IV metastatic melanoma or non-small cell lung cancer. 
Patients should be eligible for treatment with nivolumab. Patients participating in other trials with 
this agent may participate in phase one of this study, as long as this does not interfere with either 
one of the study protocols.  Patients participating in a clinical trial for nivolumab (e.g.: An open-label, 
single-arm, phase II, multicenter study to evaluate the efficacy of nivolumab in metastatic melanoma 
patients with symptomatic brain metastases) may participate in phase two of this study as well. 
The University Medical Center Groningen (UMCG) is a referral center for metastatic melanoma. 
Yearly, approximately 100 patients start systemic treatment for metastatic melanoma in this study 
center, of which 30 are eligible for nivolumab therapy each year. Out of this group approximately 1-2 
patients a month will be recruited for inclusion in this study.  
 

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5.2 Inclusion criteria 
In order to participate in this study, a subject must meet all of the following eligibility criteria: 
1. Subjects must sign informed consent prior to inclusion in this trial.  
2. “uďjeĐts ŵust ďe шϭϴ Ǉeaƌs of age aŶd ĐoŵpeteŶt to giǀe iŶfoƌŵed ĐoŶseŶt.  
3. Subjects must be diagnosed with histologically confirmed stage IV melanoma or non-small 
cell lung cancer. 
4. At least one radiologic new lesion in the brain by MRI, which should be measurable by RANO-
BM Đƌiteƌia ;loŶgest diaŵeteƌ ш ϭϬ ŵŵ aŶd peƌpeŶdiĐulaƌ diaŵeteƌ ш ϱ ŵŵͿ. LesioŶs ǁith 
prior local treatment (i.e., SRT or surgical resection) can be considered measurable if there 
has been demonstrated progression since the time of local treatment. Leptomeningeal 
involvement is allowed, but cannot be used as target lesion.  
5. At least one easy accessible metastatic melanoma lesion of which a biopsy can be taken. 
6. Subjects must be treatment-naive to nivolumab. (also as adjuvant treatment) 
7. Subjects must score at least 1 or higher on the Eastern Cooperative Oncology Group (ECOG) 
Performance Status.(25)  
8. Subjects must have adequate organ function as defined by the following laboratory values 
(determined within 28 days prior to randomization/registration): 
1. White ďlood Đells ;WBCͿ ш ϮϬϬϬ /µL 
2. Aďsolute Ŷeutƌophil ĐouŶt ;ANCͿ ш ϭϱϬϬ /µL 
3. Platelets ш ϭϬϬ ǆϭϬ3 /µL 
4. HeŵogloďiŶ ш ϵ g/dL oƌ ш ϱ.ϲ ŵŵol/L 
5. “eƌuŵ ĐƌeatiŶiŶe ч ϭ.ϱ tiŵes uppeƌ liŵit of Ŷoƌŵal ;ULNͿ oƌ ĐƌeatiŶiŶe ĐleaƌaŶĐe > ϰϬ 
ml/min (using the Cockcroft-Gault formula) 
6. Aspaƌtate aŵiŶotƌaŶsfeƌase ;A“TͿ aŶd alaŶiŶe aŵiŶotƌaŶsfeƌase ;ALTͿ ч ϯ tiŵes ULN 
7. BiliƌuďiŶ ч ϭ.ϱ tiŵes ULN ;EǆĐept patieŶts with the Gilbert Syndrome, for whom a 
maximum of ч ϯ.Ϭ ŵg/dL is acceptable) 
9. Women of childbearing potential (WOCBP) should have a negative urine or serum pregnancy 
test within 7 days prior to receiving the first administration of nivolumab. Women with non-
childbearing potential may be included if they are either surgically sterile or have been 
postŵeŶopausal foƌ ш ϭ Ǉeaƌ.  
10. WOCBP and men who are sexually active with WOCBP must agree to use appropriate 
method(s) of contraception. (see section 5.2)  
 

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5.3 Exclusion criteria 
A potential subject who meets any of the following criteria will be excluded from participation in this 
study: 
1. Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2 antibody, or any other antibody or 
drug specifically targeting T-cell costimulation or immune checkpoint pathways, except anti-
CTLA4 antibody.  
2. Subjects who have not recovered to Common Terminology Criteria for Adverse Events (CTCAE) 
v4.0 Grade 1 or better from the adverse events due to previous cancer therapy.  
3. Evidence for an active, known or suspected autoimmune disease. Subjects diagnosed with 
vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only 
requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not 
expected to recur in the absence of an external trigger are permitted to enroll. 
4. Treatment with corticosteroids in an increasing dosage in the 7 days prior to the first 
adŵiŶistƌatioŶ of Ŷiǀoluŵaď. ;A staďle oƌ deĐƌeasiŶg dosage of ч ϰ ŵg deǆaŵethasoŶe or 
equivalent is allowed. In addition, inhaled or topical steroids and adrenal replacement doses are 
permitted in the absence of active autoimmune disease.) 
5. Previous malignancies (except non-melanoma skin cancers, in situ bladder cancer, gastric or 
colon cancers, cervical cancers/dysplasia or breast carcinoma in situ) unless a complete 
remission was achieved at least 1 years prior to study entry and no additional therapy is 
required or anticipated to be required during the study period. 
6. A severe hypersensitivity reaction to prior treatment with a monoclonal antibody, or known 
hypersensitivity to study drugs components.  
7. A positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid 
(HCV antibody) indicating acute or chronic infection. 
8. Known history of testing positive for human immunodeficiency virus (HIV) or known acquired 
immunodeficiency syndrome (AIDS). 
9. Any serious or uncontrolled medical disorder or active infection that, in the opinion of the 
investigator, may increase the risk associated with study participation, study drug 
administration, or would impair the ability of the patients to receive protocol therapy. 
10. A known psychiatric or substance abuse disorder that could interfere with cancer therapy. 
11. Women of childbearing potential with a positive serum or urine pregnancy test (minimum 
sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of nivolumab. 
12. Breastfeeding women. 
13. Inability to comply with other requirements of the protocol.  
 

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5.4 Sample size calculation 
The total sample size of the study is 15 patients at maximum. A maximum of 5 patients will 
participate in phase one and 10 patients will participate in phase two. With an expected accrual rate 
of 1-2 patients per month, the intervention part of the study could be completed within 12 months. 
 
6. TREATMENT OF SUBJECTS 
6.1 Investigational product/treatment 
The intervention of this study is a [18F]PD-L1 PET scan. The radiolabeled PET tracer [18F]PD-L1 is 
developed by Bristol-Myers Squibb and will be produced in our center according to GMP guidelines. 
For additional data about the precursor material and preclinical data of the tracer we refer to the 
investigators brochure, version 1, 14 Dec 2015.  
  
6.2 Use of co-intervention  
Corticosteroids  
The use of systemic corticosteroids at baseline and during nivolumab therapy, should be avoided 
because of their potential interference with the pharmacodynamic activity and efficacy of nivolumab. 
A staďle oƌ deĐƌeasiŶg dosage of ч ϰ ŵg deǆaŵethasoŶe oƌ equivalent is allowed. In addition, inhaled 
or topical steroids and adrenal replacement doses > 4 mg daily dexamethasone equivalents in the 
absence of active autoimmune disease are permitted. 
 
Contraception methods 
WOCBP and men with reproductive potential must be willing to practice acceptable methods of birth 
control during the study. ͟WOCBP͟ is defiŶed as aŶǇ feŵale ǁho has eǆpeƌieŶĐed ŵeŶaƌĐhe aŶd ǁho 
has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not 
postmenopausal. Menopause is defined clinically as 12 months of amenorrhea in a woman over 45 in 
the absence of other biological or physiological causes. In addition, women under the age of 55must 
have a documented serum follicle stimulating hormone (FSH) level greater than 40 mIU/mL.  
WOCBP should use an adequate method to avoid pregnancy for 23 weeks (30 days plus the time 
required for nivolumab to undergo five half-lives) after the last dose of investigational drug. Men 
who are sexually active with WOCBP must use any contraceptive method with a failure rate of less 
than 1% per year. Men receiving nivolumab and who are sexually active with WOCBP will be 
instructed to adhere to contraception for a period of 31 weeks after the last dose of investigational 
product. 
 

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7. INVESTIGATIONAL PRODUCT  
See concept IMPD attached for PET radiotracer [18F]PD-L1, version 2.0, date 17-05-2016. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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8. NON-INVESTIGATIONAL PRODUCT 
8.1 Name and description of non-investigational product(s) 
See section 3.1, page 20, of the investigators brochure for nivolumab.  
 
8.2 Summary of findings from non-clinical studies 
See section 4, page 21-29, of the investigators brochure for nivolumab. 
 
8.3 Summary of findings from clinical studies 
See section 5, page 29-88, of the investigators brochure for nivolumab. 
 
8.4 Summary of known and potential risks and benefits 
For efficacy and safety results of previous clinical studies, see section 5.4 and 5.5 of the 
investigators brochure for nivolumab.  
 
8.5 Description and justification of route of administration and dosage 
 
See section 3.2.1, page 20, of the investigators brochure for nivolumab.  
 
8.6 Dosages, dosage modifications and method of administration 
See section 5.2 of this clinical trial protocol for a description of dose calculation and 
modification for nivolumab. 
 
8.7 Preparation and labelling of Non Investigational Medicinal Product 
 
See section 3.2.2., page 20-21, of the investigators brochure for nivolumab. 
 
8.8 Drug accountability 
See section 3.2.3., page 21, of the investigators brochure for nivolumab for recommended 
storage and use conditions. 
 

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9. METHODS 
9.1 Primary study parameter/endpoint 
Phase one concerns the pharmacokinetic sub-study to assess the dynamics and kinetics of the PD-L1 
tracer as measured by PET imaging in patients with inoperable melanoma treated with a PD1 
immune checkpoint inhibitor (nivolumab). For assessment of the tracer pharmacokinetics and 
optimum time for scanning, serial whole body PET scans will be acquired at baseline and six weeks 
after treatment initiation in these patients in order to determine the tracer kinetics in major organs.  
Phase two will assess the association between PD-L1 expression on PET scan and PD-L1 expression on 
IHC.  
For detailed information on study procedures, including scan sequences, we refer to paragraph 8.6 of 
this protocol. 
 
9.2 Secondary study parameters/endpoints 
Heterogeneity of tracer uptake between separate tumor lesions will be determined both for separate 
lesions within one patient (intra-patient heterogeneity) and for lesions in different patients (inter-
patient heterogeneity). 
Differences in PD-L1 expression, both assessed by PET scanning and IHC, between baseline and after 
6 weeks of treatment with a PD1 immune checkpoint inhibitor will be correlated to response to 
treatmentas measured by standard of care radiological response assessment.  
 
 
9.3 Randomisation, blinding and treatment allocation 
This trial is a single-arm study. Therefore no randomisation or blinding will take place.  A maximum of 
5 patients will be enrolled in phase one of this study. Thereafter, another 10 patients will be enrolled 
in phase two. 
 
9.4 Study procedures 
9.4.1 Patient evaluation 
Written informed consent will be obtained from patients before study entry. Patients will be 
screened for meeting all eligibility criteria. At study entry the following data are collected: medical 
history, characteristics of the primary tumor and metastases, location of a tumor lesion that could be 
biopsied, co-medication, contraceptive use, pregnancy, ECOG performance score, and a physical 
examination including vital signs, weight, length and blood pressure. To exclude pregnant women 
from the study, all WOCBP must undergo a urine pregnancy test (beta hCG) before study entry. To 

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exclude patients with an acute or chronic hepatitis infection, HBV sAg and HCVantibody will be 
determined. In addition, blood tests are acquired (e.g. complete blood count and blood chemistry), 
which are part of the regular treatment with nivolumab.  
 
9.4.2 
PET procedure and quantification of tracer uptake 
In phase one, the tracer kinetics will be measured in order to determine the optimal tracer 
distribution time and to evaluate which simplified method is best suited for the quantitative analysis 
of the tracer uptake. For this purpose, 5 patients will undergo an extended PET acquisition protocol, 
both at baseline and after 6 weeks of treatment with immunotherapy. Immediately after injection of 
the tracer a dynamic PET scan will be acquired of the chest (single bed position; 60 minutes). The 
dynamic PET scan will be followed by two total body PET scans (head to toe; 12 bed positions, 3 
minutes per bed position). The first total body PET starts at 60 minutes after tracer injection (i.e. 
immediately after the dynamic PET scan). After this scan (ca. 90-100 minutes after tracer injection), 
the patient can shortly leave the PET camera. An additional total body scan will be performed at 120 
minutes after tracer injection. The two total body scans will be used to quantify tracer uptake in 
tumors and tumor contrast throughout the body in order to establish the optimal time point for 
imaging. If during this phase of the study either one of the two total body PET scans seems obsolete 
due to low tracer availability, small differences between both scans or whatever other reason, one 
scan will be omitted to minimize burden in the following patients.  
In phase two, a single PET-scan will be performed at baseline and after six weeks of treatment at the 
optimal time point after tracer injection as determined in phase one. Both scans will be accompanied 
by a low-dose or diagnostic CT-scan for anatomic reference purposes. The scans will be performed 
one hour or two hours after tracer injection, depending on the optimal time of tracer injection as 
established in phase I. 
Before the start of the imaging procedure, a venous catheter is placed in one armand patients will be 
injected with approximately 200 MBq (0,63mL) [18F]PD-L1. Patients will be asked to drink 1 liter of 
water to promote the renal clearance of unbound tracer from the circulation in order to enhance 
signal to background ratio. Prior to scanning, patients will be asked to go to the toilet to empty their 
bladder in order to reduce the radiation burden to the patient and prevent high bladder uptake on 
the PET scan.  
Vital signs (blood pressure and heart rate) will be measured before, 10 minutes after the injection of 
[18F]PD-L1 and directly after the PET-CT scan. Blood samples will be taken before and after each PET-
CT scan to analyze complete blood count and blood chemistry. 
During the PET-scan, multiple venous samples will be taken to assess tracer metabolism. 

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Fig.2 – A: Detailed overview of the procedures in phase one of the study. Patients will be scanned both at 
baseline and after six weeks of treatment during a two hour scan protocol. B: Detailed overview of the 
procedures in phase two of the study. Again, patients will be scanned both at baseline and after six 
weeks of therapy. At both time points, only a single PET-scan will be performed. To assess PD-L1 
expression by IHC a biopsy will be taken after both PET-scans. 
 
For quantification of tracer uptake, the investigator visually identifies tumor lesions on a PET or CT 
scan and determines a region-of-interest (ROI) around these lesions. [18F]PD-L1-uptake iŶ these ‘OI͛s 
will be corrected for body weight and injected dose and quantified as standardized uptake value 

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(SUVmax and SUVmean). The absolute tracer uptake will be assessed both at baseline and six weeks 
after treatment initiation. 
9.4.3 
CT scan  
During phase two, each PET scan will be accompanied by a diagnostic CT scan. The CT scans 
performed at baseline of treatment with anti-PD1 treatment are part of care as usual. If a diagnostic 
CT scan has been performed shortly before to iŶĐlusioŶ ;чϮ ǁeeksͿ this will not be repeated. CT 
imaging consists of examination of chest, abdomen and pelvis. Response to treatment of tumor 
lesions will be evaluated according to the RECIST 1.1 criteria. 
 
9.4.4 
MRI scan 
During phase two, each PET scan will also be accompanied by a MRI scan of the brain. These MRI 
scans are also part of regular care at baseline of treatment with anti-PD1 treatment. If a recent brain 
M‘I sĐaŶ has ďeeŶ peƌfoƌŵed pƌioƌ to iŶĐlusioŶ ;чϮ ǁeeksͿ this will not be repeated at baseline. 
Before the MRI scan will be performed, gadolium will be administrated intravenously which acts as a 
contrast agent. In subjects with a contraindication for an MRI scan, this could be replaced by a 
contrast-enhanced head CT scan. 
 
 
9.4.5 
Biopsy  
In phase two of the study at least one biopsy sample will be collected from an accessible tumor 
lesion after each PET scan. If possible, these tissue samples will be obtained from the same tumor 
lesions at baseline and after 6 weeks of treatment. Ideally biopsies will be taken from both [18F]PD-
L1 PET positive as well as negative lesions within the same patient. Determination of the biopsy site 
will be based on tumor localization on previous diagnostic imaging studies and will be performed 
according to current safety criteria.  A biopsy will be performed under local anesthetics and 
ultrasonographic or CT-guidance. Biopsy material will be FFPE. 
 
9.4.6 
Immunohistochemistry 
Immunohistochemistry 
will 
be 
performed 
on 
FFPE 
tumor 
blocks 
mounted 
on 
3-
aminopropyltriethoxysilane-coated glass slides. To determine PD-L1 and PD1 expression on 
melanoma cells and tumor infiltrating immune cells respectively, these slides will be stained with 
anti-PD-L1 and anti-PD1 monoclonal antibodies. For quantitative scoring of positively stained cells, 

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the percentage of positive cells, the intensity of staining and the pattern of staining will be accounted 
for.  
 
9.5 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. 
 
 
 
 
9.6 Replacement of individual subjects after withdrawal 
Subjects that withdraw from the study will be replaced in order to achieve the number of patients 
Ŷeeded foƌ the studǇ eŶdpoiŶts; see ͚saŵple size ĐalĐulatioŶ͛.  
 
9.7 Premature termination of the study 
Premature termination will only be applied when serious unforeseen adverse events are detected 
which could be clearly attributed to the investigational product, and which prompt a premature 
termination of the study.  

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10. SAFETY REPORTING 
10.1 Section 10 WMO event 
In accordance to section 10, subsection 1, of the WMO, the investigator will inform the subjects and 
the reviewing accredited METC if anything occurs, on the basis of which it appears that the 
disadvantages of participation may be significantly greater than was foreseen in the research 
proposal. The study will be suspended pending further review by the accredited METC, except insofar 
as suspeŶsioŶ ǁould jeopaƌdise the suďjeĐts͛ health. The iŶǀestigatoƌ ǁill take Đaƌe that all suďjeĐts 
are kept informed.  
 
10.2 AEs, SAEs and SUSARs 
10.2.1 
Adverse events (AEs) 
AEs are defined as any undesirable experience occurring to a subject during the study, whether or 
not considered related to the investigational product. All AEs reported spontaneously by the subject 
or observed by the investigator or his staff will be recorded. 
 
10.2.2 
Nonserious adverse events 
A nonserious adverse event is an AE not classified as serious. The collection of nonserious AE 
information should begin at initiation of study drug. All nonserious AEs (not only those deemed to be 
treatment-related) should be collected continuously during the treatment period and for a minimum 
of 100 days following the last dose of study treatment.  
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they become 
serious. Follow-up is also required for nonserious AEs that cause interruption or discontinuation of 
study drug and for those present at the end of study treatment as appropriate.  
 
10.2.3 
Serious adverse events (SAEs) 
All SAEs reported spontaneously by the subject or observed by the investigator or his staff will be 
recorded according to CTCAE v4.0. A SAE is any experience that suggests a significant hazard, 
contraindication, side effect or precaution. It is any AE that at any dose fulfills at least one of the 
following criteria: 
 
results in death; 
 
is life threatening (at the time of the event); 
 
ƌeƋuiƌes hospitalisatioŶ oƌ pƌoloŶgatioŶ of eǆistiŶg iŶpatieŶts͛ hospitalisatioŶ; 

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 
results in persistent or significant disability or incapacity; 
 
is a congenital anomaly or birth defect; 
 
is a potential drug induced liver injury (DILI); 
 
is a suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via 
the study drug; 
 
is a pregnancy, overdose, or secondary cancer; 
 
Any other important medical event that may not result in death, be life threatening, or 
require hospitalization, may be considered a serious adverse experience when, based upon 
appropriate medical judgement, the event may jeopardize the subject or may require an 
intervention to prevent one of the outcomes listed above. 
 
Medical and scientific judgment should be exercised in deciding whether expedited reporting to the 
sponsor is appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the patient or 
requires intervention to prevent one of the outcomes listed in the definitions above. These situations 
should usually be considered serious. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not 
result in hospitalization; or development of drug dependency or drug abuse. An unexpected Adverse 
Event is one, the nature or severity of which is not consistent with the applicable product information. 
 The causal relationship to study drug is determined by a physician and should be used to assess all 
adverse events (AE). The causal relationship can be one of the following: 
- Related: There is a reasonable causal relationship between study drug administration and the AE. 
- Not related: There is not a reasonable causal relationship between study drug administration and 
the AE.  
The term "reasonable causal relationship" means there is evidence to suggest a causal relationship. 
The term severe is a measure of intensity, thus a severe adverse event is not necessarily serious. For 
example, nausea of several hours' duration may be rated as severe, but may not be clinically serious. 
FolloǁiŶg the suďjeĐt͛s ǁƌitteŶ ĐoŶseŶt to paƌtiĐipate iŶ the studǇ, all “AEs, ǁhetheƌ ƌelated oƌ Ŷot 
related to study drug, must be collected, including those thought to be associated with protocol-
specified procedures. All SAEs must be collected that occur within 100 days of discontinuation of 
dosing.  
In addition, a SAE that oĐĐuƌs afteƌ this tiŵe, if ĐoŶsideƌed ƌelated to test ͞dƌug͟, should ďe ƌepoƌted. 
Such preliminary reports will be followed by detailed descriptions later which will include copies of 
hospital case reports, autopsy reports and other documents when requested and applicable. For 

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SAEs, the following must be assessed and recorded on the adverse events page of the Case Report 
Form: intensity, relationship to test substance, action taken, and outcome to date.  
 
The sponsor will report the SAEs through the web portal ToetsingOnline to the accredited METC that 
approved the protocol, within 15 days after the sponsor has first knowledge of the serious adverse 
reactions.  
 
SAEs that result in death or are life threatening should be reported expedited. The expedited 
reporting will occur not later than 7 days after the responsible investigator has first knowledge of the 
adverse reaction. This is for a preliminary report with another 8 days for completion of the report.  
 
Besides ƌepoƌtiŶg to the aĐĐƌedited METC, all “AE͛s that oĐĐuƌ folloǁiŶg the suďjeĐt͛s ǁƌitteŶ ĐoŶseŶt 
to participate in the study through 100 days of discontinuation of dosing must be reported to the 
sponsor BMS Worldwide Safety.  (email: Worldwide.Safety@BMS.com; fax: 609-818-3804) 
All SAEs must be collected that occur during the screening period. If applicable, SAEs must be 
collected that relate to any protocol-specified procedure (eg, a follow-up skin biopsy). The 
investigator should report any SAE that occurs after these time periods that is believed to be related 
to study drug or protocol-specified procedure.  
SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS within 
24 hours. SAEs must be recorded on BMS or an approved form; pregnancies on a Pregnancy 
Surveillance Form. 
If only limited information is initially available, follow-up reports are required. (Note: Follow-up SAE 
reports should include the same investigator term(s) initially reported.)  
If an ongoing SAE changes in its intensity or relationship to study drug or if new information becomes 
available, a follow-up SAE report should be sent within 24 hours to the BMS (or designee) using the 
same procedure used for transmitting the initial SAE report.  
All SAEs should be followed to resolution or stabilization. 
10.2.4 
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); 

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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: 
- 
Summary of Product Characteristics (SPC) for an authorised medicinal product; 
- 
IŶǀestigatoƌ͛s BƌoĐhuƌe (IB) for an unauthorised medicinal product. 
 
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 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.  
 
The principal investigator (PI) is ƌespoŶsiďle foƌ ƌepoƌtiŶg “U“A‘͛s. All ĐooƌdiŶatiŶg iŶǀestigatoƌs of 
suďĐeŶteƌs should iŶfoƌŵ the pƌiŶĐipal iŶǀestigatoƌ as sooŶ as possiďle. All “U“A‘͛s aƌe ƌepoƌted 
unblinded to the competent authorities.  
 

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10.3 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. 
 
10.4 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  
 

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11. STATISTICAL ANALYSIS 
This is an exploratory, feasibility study that serves to provide base case statistics for further 
prospective research. Primarily descriptive statistics will be used. Demographic and baseline 
characteristics will be summarized using means, standard deviations, medians, and ranges for 
continuous variables, and proportions for categorical variables. The PET results will be both 
qualitatively and quantitatively assessed in 15 patients. Categorical data will be assessed using the 
Fisheƌ͛s eǆaĐt test. CoŶtiŶual data ;paiƌed aŶd uŶpaiƌedͿ ǁill ďe assessed usiŶg ŶoŶ-parametrical 
tests (i.e. Mann-Whitney U test and Kruskall-Wallis test). 
 
11.1 Primary study parameter(s) 
Tracer pharmacokinetics and the optimal time for scanning will be determined from the data 
obtained by the serial PET scans in first 5 patients. Output parameters are the radiation absorbed 
dose to major organs, the effective dose equivalent for patients, the recommended maximum 
injected dose for [18F]PD-L1 and the optimal time point for scanning after tracer administration. 
PD-L1 expression in melanoma tumor lesions will be quantified by measuring tracer uptake in tumor 
lesions. Tracer uptake will be corrected for body weight and injected dose and quantitatively 
assessed as standardised uptake value (SUVmean with associated standard deviation and SUVmax), 
which is calculated using the formula: [tissue activity concentration (MBq/g)]/[(injected dose 
(MBq)/bodǇ ǁeight ;gͿ]. “UV ǁill ďe ĐalĐulated foƌ all pƌedefiŶed ‘OI͛s oŶ the PET-CT scan at 
baseline. On the PET-CT scan at week 6 of treatment, SUV will be determined for all lesions detected 
at baseline as well as all newly detected tumor lesions.  
Tumor uptake of [18F]PD-L1 will be correlated with the amount of PD-L1 expression of melanoma 
cells and PD-1 and PD-L1 expression on tumor infiltrating immune cells in melanoma lesions. PD-L1 
and PD1 expression will be measured by immunohistochemistry. Results of immunohistochemical 
staining will be described as a semi-quantitative score using the percentage of positive cells 
(continuous variable), intensity and pattern of staining (discrete variable). This semi-quantitative 
score will then be correlated to SUV of the corresponding lesion on the [18F]PD-L1 PET. Correlation 
will be expressed as a Pearson/Spearman correlation coefficient depending on distribution of data. 
Results will be displayed in graphs. 
 
11.2 Secondary study parameter(s)  
Heterogeneity between tracer uptake of separate tumor lesions will be determined. For this purpose 
the absolute difference in SUV between the two PET scans will be determined for all separate lesions 
and will be visualised in a table. Heterogeneity of this absolute difference in SUV will be analysed for 

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lesions in one patient (intra-patient heterogeneity) and for lesions between patients (inter-patient 
heterogeneity).  
Although the study population is too small to generate statistical relevant information, the ability of 
PD-L1 expression to predict response to anti-PD1 treatment will be assessed as a secondary 
parameter. For this purpose the different lesions identified on the first PET-CT scan, will be 
qualitatively scored as responding (stable disease, partial or complete regression) or non-responding 
(progressive disease) according to the RECIST 1.1 criteria. The measured response will then be 
correlated to the absolute increase in SUV between the two PET scans for PD-L1 expression on PET 
and response will be correlated to the difference in immunohistochemical score for PD-L1 expression 
in tumor tissue samples.  

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12. ETHICAL CONSIDERATIONS 
12.1 Regulation statement 
The study will be conducted according to the principles of the Declaration of Helsinki (Amended by 
the 64th WMA General Assembly, Fortaleza, Brazil, October 2013) and in accordance with the 
Medical Research Involving Human Subjects Act (WMO) and other guidelines, regulations and Acts. 
 
12.2 Recruitment and consent 
Treating physicians can refer a patient to the investigator (medical doctor) for participation in the 
study. Information about the study will appear on the website of the medical oncology department 
(www.medischeoncologiegroningen.nl).  
Patients will be informed by one of the investigators (medical doctor) and under the supervision of 
the principle investigator. Patients will be informed orally during a patient visit in the UMCG and will 
receive a patient information letter (attached as a separate document). Patients will have a minimum 
of 1 week to consider their decision. When a patient wants to participate a written informed consent 
form has to be signed (attached as a separate document). After completion of the study procedures 
the patient will be referred back to the treating physician.  
 
12.3 Objection by minors or incapacitated subjects (if applicable) 
All subjects will be шϭϴ years and competent. 
 
12.4 Benefits and risks assessment, group relatedness 
Molecular imaging with a PET scan is an upcoming technique for obtaining non-invasive whole body 
information about specific molecular targets. In this imaging study we want to visualize PD-L1 
expression in tumor lesions of patients with metastatic melanoma. This tumoral PD-L1 expression 
could serve as a predictor of response to anti-PD1 treatment Results of this study could provide 
valuable information about the whole body distribution of PD-L1 in tumor lesions and heterogeneity 
in this distribution. In addition, this study will explore how intratumoral PD-L1 and PD1 expression is 
influenced by anti-PD1 treatment. 
Patients will not benefit from participation in this study directly, but their participation helps to 
develop a new imaging technique which could provide more insights in PD-L1 expression in tumor 
lesions and predictive value of this PD-L1 expression. 
 

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Patients will be treated with anti-PD1 as part of their regular treatment or in the context of a clinical 
trial. So, this treatment will not cause any additional risk or burden to the patient in this imaging 
study. Patients will also get regular follow-up to assess disease control. 
The tracer was well tolerated in pre-clinical toxicology studies performed in cynomolgus monkeys. 
For detailed information, we refer to the IB, version 1, 14 Dec 2015. 
The expected applied injected activity of [18F]PD-L1 is 200 MBq, as is the case for most other 18F-
labeled tracers. This dose will be used in phase one of the study and could be changed according to 
the pharmacokinetics results for patients in phase two of the study. The radiation burden for a dose 
of 200 MBq is estimated to be comparable to that of other 18F-labeled PET tracers (approximately 
4.4 mSv). Patients will receive 2 serial PET scans each accompanied by a low dose CT scan which adds 
up to a total dose of 11.8 mSv. The radiation burden of these patients complies with category III 
(moderate risk) according to the International Commission on Radiological Protection (ICRP) 
guidelines (ICRP publication 62). According to the investigators, the radiation burden in this category 
of patients is justified by the information that can be obtained from this study, previously described. 
Biopsies are mandatory in phase two of this study. This is an invasive procedure. Preferably biopsies 
will be taken form easy accessible lesions to minimize the burden to the patient. Patients will be 
informed explicitly about potential safety issues. Although biopsies are generally considered to be 
safe, it could be a painful intervention and carries the risk of bleeding at the puncture site.  
Whenever possible, all procedures that are part of the study protocol will be planned on a day that 
the patient already has a regular visit to the hospital as part of their treatment. 
 
12.5 Compensation for injury 
The sponsor/investigator has a liability insurance which is in accordance with article 7, subsection 6 
of the WMO. 
 The sponsor (also) has an insurance which is in accordance with the legal requirements in the 
Netherlands (Article 7 WMO and the Measure regarding Compulsory Insurance for Clinical Research 
in Humans of 23th June 2003). This insurance provides cover for damage to research subjects 
through injury or death caused by the study. 
The insurance applies to the damage that becomes apparent during the study or within 4 years after 
the end of the study. 
 
12.6 Incentives (if applicable) 
For each day of patient related study procedures, the subjects will receive compensation for 
tƌaǀelliŶg eǆpeŶses ;€ Ϭ.ϭϵ/kŵͿ aŶd a tiĐket foƌ fƌee paƌkiŶg. 

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13. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
13.1 Handling and storage of data and documents 
As a result of the regulations for radiation exposure/ safety, the information that is obtained at the 
Department of Nuclear Medicine and Molecular Imaging will not be stored anonymously. However, 
personal information will only be accessible for medical doctors affiliated to that department and 
handled confidentially. Histological material that is obtained during the study is regarded as routine 
clinical information and kept for a longer period according to standard protocols. This material is 
accessible for pathologists.  
For other data management, study subjects will receive a code. The code will consist of the study ID 
number followed by patient number (1-15) The key to the code (number linked to patient) is 
safeguarded by the investigator. The study code assigned to the patients will also be used in the 
collection of all the study results by the investigator who will perform the data-analysis. An overview 
of all data and data-analysis is made according to this code, so that the final results cannot be traced 
back to the patients by another person than the investigators involved in the study (in compliance 
with the Dutch Personal Data Protection Act).  
Data will be stored for a maximum period of 15 years after the study is finished.  
 
13.2 Monitoring and Quality Assurance  
On-site monitoring will take place conform the NFU (Nederlandse Federatie van Universitaire 
Medisch Centra)-guideliŶe ͞KǁaliteitsďoƌgiŶg ǀaŶ ŵeŶsgeďoŶdeŶ oŶdeƌzoek ϮϬϭϬ͟ ďǇ the appoiŶted 
monitor. Monitoring will take place to assure the quality and validity of the research data. The 
monitor will perform source data verification on the research data by comparing the data entered 
into the CRF with the available source documentation and other available documents. Source 
documents are defined as the patieŶt͛s hospital medical records, clinician notes, laboratory print 
outs, digital and hard copies of imaging, memos, electronic data etc. The monitor will verify the 
following items (100%): Patient flow (inclusion speed and dropout rate); Informed consent forms 
(presence, dates, signatures); Trial Master File and Investigator Files (presence of all documents), in-
/exclusion criteria (using source documents); SAEs / SUSARs (number, missed, reporting procedures); 
study product (administration, accountability). After each control the monitor will send a written 
report to the sponsor (including a summary; quality assessment; summary of findings, deviations and 
shortcomings; possible solutions to warrant compliance with the protocol; final conclusion). 
 

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13.3 Amendments  
A ͚suďstaŶtial aŵeŶdŵeŶt͛ is defiŶed as aŶ aŵeŶdŵeŶt to the teƌŵs 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.  
 
13.4 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.  
 
13.5 End of study report 
The sponsor will notify the accredited METC and the competent authority of the end of the study 
ǁithiŶ a peƌiod of ϵϬ daǇs. The eŶd of the studǇ is defiŶed as the last patieŶt͛s last ǀisit.  
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.  
 
13.6 Public disclosure and publication policy 
The authors have no conflict of interest, no financial interest and no arrangement or affiliation with 
any commercial organization that may have a direct or indirect interest in the outcome of the study. 

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14. STRUCTURED RISK ANALYSIS  
14.1 Potential issues of concern 
14.1.1 
Level of knowledge about mechanism of action 
The mechanism of action of the [18F]PD-L1 PET tracer has been studied extensively in preclinical 
models. See section 4.1, page 13 – 23 of the IB for PD-L1 Adnectin PET Tracer (BMS-986192) for 
detailed information. 
 
14.1.2 
Previous exposure of human beings with the test product(s) and/or products with 
a similar biological mechanism 
No clinical studies have been conducted with the [18F]PD-L1 PET tracer. This is the first study 
assessing the use of the [18F]PD-L1 PET tracer in human beings. (IB: section 5, page 28.) 
 
14.1.3 
Can the primary or secondary mechanism be induced in animals and/or in ex-vivo 
human cell material? 
The feasibility of the [18F]PD-L1 PET tracer has been shown in both mouse xenograft and cynomolgus 
monkey studies, as well as in human tissue (non small cell lung cancer samples). For more 
information see section 4.1.1.1 and 4.1.1.2, page 13 – 17 of the IB for PD-L1 Adnectin PET Tracer 
(BMS-986192).  
 
14.1.4 
Selectivity of the mechanism to target tissue in animals and/or human beings 
Tissue binding studies have been performed in vivo in cynomolgus monkeys and mice xenograft 
models and in vitro using human tissue. The [18F]PD-L1 PET tracer is highly selective for both 
cynomolgus monkey and human forms of the PD-L1 extracellular domain, but not to the extracellular 
domain of murine PD-L1. The [18F]PD-L1 PET tracer has shown high uptake in kidney, L2987 
xenograft, lung and bone. For more detailed information see section 4.1, page 13 – 23 of the IB for 
PD-L1 Adnectin PET Tracer (BMS-986192) for detailed information. 
 
14.1.5 
Analysis of potential effect 
The tracer was well tolerated in pre-clinical toxicology studies performed in cynomolgus monkeys. 
(IB: section 4.3.1, page 26 and 27.) Genotoxicity and reproductive and developmental toxicity were 
not assessed due to reasons listed in sections 4.3.2 and 4.3.3, page 27 and 28 of the IB for PD-L1 
Adnectin PET Tracer (BMS-986192).  

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14.1.6 
Pharmacokinetic considerations 
Results of pre-clinical pharmacokinetic studies can be found in section 4.2, page 24 and 25 of the IB 
for PD-L1 Adnectin PET Tracer (BMS-986192). 
 
14.1.7 
Study population 
Our study population consists of stage IV melanoma patients with symptomatic brain metastases. 
Study subjects are at least 18 years of age and must understand and sign informed consent prior to 
study inclusion. For detailed information on the study population concerned we refer to section 4.1 - 
4.3, page 15 – 17 of this protocol. 
 
14.1.8 
Interaction with other products 
Pharmacokinetic drug interactions have not been evaluated. (IB: section 4.2.5, page 25.) 
 
14.1.9 
Predictability of effect 
Since the investigational product in this study is a diagnostic agent, without an expected 
pharmacological effect, no biomarkers are used to predict such an effect. 
 
14.2 Synthesis 
This is the first time the [18F]PD-L1 PET tracer is tested in a clinical study, therefore no toxicology and 
overall risk data is available on the use of this product in human beings. Pre-clinical testing in 
cynomolgus monkeys has shown no toxicologic findings, as stated before. This toxicity study has 
shown a favourable safety profile in monkeys with a high safety margin relative to the anticipated 
tracer dose used in the human population.There is no available information concerning overdose 
with the study tracer. There is no specific antidote available. Upon suspicion of overdose and/or 
adverse reactions based on symptoms and/or signs supportive medical management should be 
provided. For further information see section 4.3 through 4.5, page 25 – 28 of the IB for PD-L1 
Adnectin PET Tracer (BMS-986192). 
 
 
 
 

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