"An Exploratory Study Regarding the Use of the Biomarker Dopamine Transporter (DAT) for Image Diagnosis of Clear Cell Renal Cell Carcinoma"
Phase: PHASE2
Conditions: Clear Cell Renal Cell Carcinoma
Sponsor: Region Skane

Sponsors protocol date 2016-12-21 
 
Version 3 
EudraCT: 2016-005182-31 
 
 
 
 
Study protocol 
 
 
 
Study ID: RCCSCAN 
 
 
 
 
"An exploratory study regarding the use of the biomarker DAT for image diagnosis of clear 
cell renal cell carcinoma" 
 
 
 

Sponsors protocol date 2016-12-21 
 
Version 3 
EudraCT: 2016-005182-31 
Contact information 
 
Sponsor:  
Lund Universitet 
Professor Håkan Axelson 
Avdelningen för Translationell Cancerforskning 
Institutionen för laboratoriemedicin 
Medicon Village 404:A3 
223 63 Lund 
hakan.axelson@med.lu.se 
 
Principal Investigator:  
Cheif Physician Peter Elfving  
Urologiska kliniken  
Skånes Universitetssjukhus  
Jan Waldenströms gata 7 
205 02 Malmö 
peter.elfving@med.lu.se 
 
Monitor 
Kliniska Studier Sverige –Forum Söder 
Region Skånes Kompetenscentrum för klinisk forskning,  
Universitetssjukhuset 
221 85 Lund 
 
Other Clinical expertise: 
 
External reviewer of CT and SPECT-material  
Cheif Physician Ola Thorsson 
Klinisk fysiologi Malmö 
Skånes universitetssjukhus 
Ingång 44, plan 3 
205 02 Malmö 
E-post: ola.thorsson@med.lu.se 
 
Responsible for person and radiation protection and for DaTSCAN delivery  
Medical Physicist Sigrid Leide Svegborn  
Skånes Universitetssjukhus  
Strålningsfysik 
Inga Marie Nilssons gata 49 
205 02 Malmö 
sigrid.leide_svegborn@med.lu.se 
 
Responsible for DaTSCAN-administration 
Head of unit Margareta Anicin 
Klinisk Fysiologi och Nuklearmedicin 
Inga Marie Nilssons gata 49 

Sponsors protocol date 2016-12-21 
 
Version 3 
EudraCT: 2016-005182-31 
205 02 Malmö 
margareta.anicin@skane.se 
 
Responsible radio-pharmacist 
Leg. Apotekare Lars Söderberg 
Jan Waldenströms gata 5, PL8 
205 02 Malmö 
lars.soderberg@skane.se 
 
 
Coordinator 
Jennifer Hansson 
Avdelningen för Translationell Cancerforskning 
Institutionen för laboratoriemedicin 
Medicon Village 404:A3 
223 63 Lund 
jennifer.hansson@med.lu.se 
 
Synopsis 
 
Titel 
"An exploratory study regarding the use of the biomarker DAT for image 
diagnosis of clear cell renal cell carcinoma" 
 
Developmental 
Phase 
Phase 2 
Background 
The background to why the study should be done 
Kidney cancer affects approximately 1000 people a year in Sweden and 
globally, approximately 340,000 people are diagnosed with this disease. 
The most common form of kidney cancer is clear cell renal cell 
carcinoma (ccRCC), which accounts for about 80% of all cases. Despite 
some treatment progress, over 40% of patients who suffer from kidney 
cancer die. The presence of this tumor form is increasing globally and 
the annual growth rate is estimated at 6.25% in the period 2013-2023. 
Localized kidney cancer has good prognosis; The tumor, or tumor-
bearing kidney is usually surgically removed. However, the symptoms of 
renal cancer are diffuse and in about 25% of cases, the disease has 
already spread beyond the kidney at the time of diagnosis. An 
additional 25% of patients with localized disease later display 
metastases, although the first analysis showed that the disease was 
limited to the kidney. For patients with metastatic disease, the 
prognosis is very poor, as kidney cancer does not respond to common 
cancer treatments such as cytostatics and radiation and less than 10% 
of these patients are expected to survive for five years. It is therefore 
crucial to be able to clarify the spread of the disease. Today there are 
no diagnostic methods that can specifically detect kidney cancer and 
distinguish between subtype of renal cancer. Small metastases are likely 

Sponsors protocol date 2016-12-21 
 
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EudraCT: 2016-005182-31 
to be missed by today's methods. The need for new diagnostic methods 
is therefore eminent. 
 
We have identified the molecule Dopamine Transporter (DAT) as a new, 
highly specific, biomarker for clear cell kidney cancer. This molecule is 
usually only expressed in the brain of dopaminergic neurons, but we 
have now shown that it is found to be very high in clear cell kidney 
cancer, but not in other cancers. DAT is used today in the diagnosis of 
Parkinson's disease. DaTSCAN is a radioactively labeled substance that 
binds to DAT and thus to dopaminergic neurons. The signal from the 
binding can be detected using SPECT camera and a decreased signal is 
evidence of loss of dopaminergic neurons and thus Parkinson's disease, 
which then can be distinguished from other neurodegenerative 
diseases. This study aims at investigating whether clear cell kidney 
cancer can be detected by a DaTSCAN analysis, where in this case an 
increased signal is expected, unlike Parkinson's diagnostics 
 
 
 
Study design 
Open single arm trial with a small number of patients (10) for proof of 
concept of the use of DaTSCAN for the detection of clear cell RCC. 
Recruited patients with suspected dissiminated kidney cancer will, after 
informed consent to participate in the study, be investigated using CT 
and DaTSCAN followed by SPECT. DaTSCAN is injected intravenously and 
followed by SPECT examination 5h later. The images from the DaTSCAN 
investigation will be analyzed and anatomically compared to CT 
examination of the patient. Any side effects of the study will be 
reported. 
 
 
 
Objectives 
The main objective is to investigate whether DaTSCAN with subsequent 
SPECT can detect elevated DAT levels in at least one lesion identified 
with CT in patients with clear cell renal cell carcinoma, as assessed by 
pathologist?  
DaTSCAN signal will be seen as positive, when displaying intensity ≥3ggr 
higher than the background and correlating anatomically with at least 
one lesion found with CT.  
 
DaTSCAN is used routinely to detect the loss of dopaminergic neurons 
in the striatum of patients with clinically uncertain Parkinsonian 
Syndromes. The active substance in DaTSCAN, Ioflupane specifically 
binds to DAT. By analyzing the focal uptake of Ioflupane (123I) with 
SPECT / CT the progression of the disease may be clarified. In light of 
our findings that clear cell renal cancer express significantly elevated 
levels of DAT, we postulate that DaTSCAN can be used for detection of 
clear cell renal cell carcinoma. 
 
The exploratory objective is to investigate whether: 

Sponsors protocol date 2016-12-21 
 
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• DaTSCAN with subsequent SPECT, by detecting elevated levels of DAT 
in clear cell renal cancer, can be used to distinguish clear cell renal 
cancer from other subtypes of renal cancer such as papillary renal cell 
cancer, chromofob kidney cancer and benign tumors such as 
oncocytoma? 
 
• Surgically removed DaTSCAN positive lymph nodes exhibit infiltration 
of clear cell renal cell carcinoma cells, regardless of the CT status?  
 
• DAT-mRNA expression in primary tumor correlate with DaTSCAN 
signal where the surgically removed tumor material with high DaTSCAN 
intensity also exhibit high mRNA levels of DAT? 
 
 
Study population 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and 
exclusion criteria 
This study is an exploratory single-arm study at Skåne University 
Hospital. The study intends to include 10 patients, if one of the research 
subjects withdraws from the study, this subject will be replaced so that 
the number of persons is 10 in total. After 10 analyzed patients, an 
evaluation is made. If less than 8 patients out of the 10 analyzed have 
been diagnosed as ccRCC by pathologist, an additional 3 patients will be 
included. Each patient will be evaluated continuously after completion 
of the study. For ethical reasons, the study will be terminated if 4 
patients diagnosed with clear cell kidney cancer by pathologist, all 
display negative DaTSCAN signal in primary tumor. 
 
The patients / research subjects will be recruited through the Urological 
Clinic in Malmö. 
 
The DaTSCAN study will be conducted at the department of Clinical 
Physiology / Nuclear Medicine VO Image and Function in Malmö 
 
Pathologic assessment of surgically removed material from each study 
subject will be obtained from the Pathological Clinic in Malmö 
 
 
This study plans to include subjects that comply to the following 
inclusion and exclusion criteria:  
 
Inclusion criteria 
-suspected kidney cancer diagnosis 
-suspected spread of the cancer 
-the patient is scheduled for surgery alternatively biopsy of kidney 
tumor 
-the patient is 18 years or older 
-the patient has given their consent to participate in the study 
 
Exclusion criteria 
-known or suspected allergy to the active substance in DaTSCAN, 

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ioflupane or any of the following ingredients: 
• Sodium acetate 
• Acetic acid 
• Ethanol 
-the patient suffers from moderate to severe liver disease with liver 
enzymes (transaminases)> 2 times the upper limit 
-the patient suffers from moderate to severe renal impairment and 
exhibits GFR <40 
-the patient is medicated for Parkinson's disease 
-the patient is medicated with any of the following medications: 
• Amphetamine 
• benzatropine 
• Buproprion 
• Cocaine 
• mazindol 
• Methylphenidate 
• Phentermine 
• Sertraline 
• levodopa (Sinemet, Pharma Copa, Atamet, Stalevo, Madopar, Prolopa) 
 
-the patient is /or plans to become pregnant 
-breastfeeding 
-the patient suffers from mental inability, unwillingness or language 
difficulties resulting difficulty in understanding the meaning of taking 
part in the study 
 
 
 
Methodology  
Patients with suspected renal cancer are screened for the suitability to 
participate in the study.  
After informed consent, a 3-phase CT examination of abdominal and 
thoracic baseline for tumor burden is performed. If an equivalent CT 
scan was performed in Region Skåne <28 days before the inclusion date, 
this study will be the basis of the baseline for tumor burden.  
Thereafter, the patient is scheduled for DaTSCAN examination, which is 
performed before any surgery. Prior to DaTSCAN injection the patient 
takes potassium iodide tablets, according to local clinical practice for 
DaTSCAN studies, to protect the thyroid gland. At the time of 
investigation of DaTSCAN, the patient is slow-paced injected with the 
DaTSCAN solution in the arm, not faster than 15 seconds. The patient 
then waits for 5h before image diagnosis with abdomen / thoracic 
SPECT / CT is performed.  
Possible side effects are documented.  
The collected image material is analyzed and compared for anatomical 
localization with previously performed CT examination.  
 

Sponsors protocol date 2016-12-21 
 
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EudraCT: 2016-005182-31 
Two days after the DaTSCAN study, the patient is contacted for follow-
up of possible side effects following the study. Pathological assessment 
statement collected from pathologist after surgery / biopsy.  
If the patient has consented to biobanking tissue samples from 
removed tumor according to ethical approval: LU680-08 and LU289-07, 
mRNA levels of DAT are also analyzed for these samples.  
 
The study closes after 10 patients are subjected to DaTSCAN-
examination, the results have been analyzed and pathological responses 
are obtained. The study is expected to end after 1 year. 
For ethical reasons, an early stopping rule is applied if four patients with 
pathologically verified ccRCC display negative signal from the DaTSCAN 
examination, the study is in that case ended.  
 
Test product 
Test product, dose and mode of administration, batch number: 
Test product 
Substance Generic Name: Ioflupan (I-123), Product Name: DaTSCAN, 
ATC Code: V09AB03 
Pharmaceutical form and strength: Solution for injection 74MBq/ml, 
Manufacturer: GE Healthcare 
DaTSCAN was ordered from GE Healthcare, and provided with patient-
specific labeling by the clinician responsible for administering DaTSCAN 
to patient. 
 
Mode of administration: 
The patient takes potassium tablets prior to the examination, to protect 
the thyroid gland. At the time of the DaTSCAN examination, the patient 
is injected intravenously at slow rate with 185MBq DaTSCAN solution. 
Using a dose calibrator, 185MBq of DaTSCAN is drawn into the syringe 
to be given to the research person. A label is printed and put on the 
syringe with the following information: patient name, drug, batch, dose 
and draw time. Thereafter, the drug is administered directly to the 
patient. Afterwards, the remaining activity in the syringe is measured 
and the exact dose is recorded in the patient's journal. The patient then 
waits for 5h before performing diagnostic examination with SPECT. 
 
Evaluations 
Criteria for evaluation: 
Each patient is continuously evaluated after completion of the 
DaTSCAN-examination and analysis. 
Efficacy 
Analysis of the image material from the SPECT study 
Signal from DaTSCAN is quantified and compared with an internal 
control in the form of the previous CT imaging. DaTSCAN signal is 
considered positive when ≥3 times higher than background and 
correlating anatomically with at least one lesion found with CT.  
 
Pathological assessment 

Sponsors protocol date 2016-12-21 
 
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The patient's surgically removed tumor/metastasis will be examined by 
a pathologist for kidney cancer subtype determination. This assessment 
will be compared to the DaTSCAN expression. If patients with 
pathologically verified ccRCC tumor also have positive DaTSCAN signal, 
the DaTSCAN study will be considered to detect clear cell kidney cancer. 
 
mRNA levels of DAT in tumor tissue from biobank 
In the cases where the recruited research persons have given consent 
to that material from surgery/biopsy is save for research (biobank) in 
accordance with licence number LU680-08 and LU289-07, these 
samples will be requested from the biobank. These samples will be 
examined for mRNA levels of DAT and then compared to DaTSCAN 
signal in the same tissue to investigate any correlation.  
 
Safety 
Potential Adverse Events is registered at each study visit.  
• When injecting DaTSCAN (Ioflupan I123) 
• Immediately after the SPECT investigation  
• 2 days after the DaTSCAN survey (through telephone interview 
from research nurse) 
The incidents may be observed by a doctor / nurse or reported by the 
subjects themselves. At each study visit (above), an open question is  
asked to the subjects: "Have you had any health problems since taking 
potassium iodide?" 
 
End of Study 
The patient / research subject can end their participation in the study at 
any time without any consequences for his/hers further treatment. 
 
The doctor / sponsor may suspend the patient's participation in the 
study at any time e.g. because of adverse effect or that the subjects 
does not comply the study protocol. 
 
If the research subject exhibits hypersensitivity reaction of the DaTSCAN 
injection, the patient does not need to proceed to SPECT examination. 
 
Statistical plan 
As this is an exploratory study with a low number of patients, thus there 
is no basis for a power calculation. However, assuming that the 
proportion of clear cell kidney cancer (ccRCC) is 80% of all kidney cancer 
cases, we plan to include 10 patients with the probability that at least 6 
patients had ccRCC of 96,7% and with a probability of 8 ccRCC patients 
of 67,8%. The results will be presented with descriptive statistics. An 
exploratory objective is whether DaTSCAN can be used for differential 
diagnosis of renal cancer. With a recruitment of 10 renal cancer 
patients, there is 62.4% probability that we include 2 patients of non-
clear cell subtype. 
 

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Adverse Events 
Incidents will be registered at each study visit. That is on the following 
occasions: 
 
When injecting DaTSCAN (Ioflupan I123) 
Immediately after the SPECT investigation 
2 days after the DaTSCAN investigation 
 
On these occasions, open questions will be asked to the subjects: "Have 
you had any health problems since taking potassium iodide?" 
 
The incidents may be observed by a doctor / nurse or reported by the 
subjects themselves. Incidents are entered into patient records and 
subsequently recorded in CRF. Assessment of relationship, severity and 
seriousness is done by the investigator in CRF. As a minimum, registered 
for each incident: description of the incident, start and stop, 
relationship, severity, and if considered serious, actions and outcomes. 
All serious side effects will be followed until they are restored or until 
confirmed by the examiner as no longer necessary to follow these 
incidents. 
 
Potential 
benefit: 
In a longer perspective, a new method of renal cancer imaging would be 
of great importance Today, many cases of small metastases that require 
systemic treatment missed. Through a more accurate picture of the 
spread of the disease, treatment could be adapted.