Clinical pilot study to determine the feasibility of detecting pancreatic beta cells using Exendin-4-800CW targeting the glucagon-like peptide 1 receptor for future application of molecular fluorescence guided surgery in insulinoma patients (BETA-light)

Reliable visualization of beta cells would benefit the optimization of
treatment of patients with adult endogenous hyperinsulinemic hypoglycaemia
(AHH). By visualizing molecular changes that accompany disease, molecular
imaging holds the promise to be able to better characterize disease states and
extent at an earlier time and with lower required contrast differences than
current (anatomical) imaging modalities. Tumour-specific intraoperative
near-infrared (NIR) fluorescence techniques have two major advantages: they not
only give visual feedback to the surgeons, but also provide quantitative
measurements that can be analysed for the presence of positive margins and
microscopic residual disease. Therefore, this novel approach could lead to a
minimization of side-effects from the surgical treatment, decrease recurrence
rates and ultimately improve disease free survival. Image guided surgery
requires optical tracers with a considerably high target-to-background ratio in
order to enable differentiation between diseased and healthy tissue. The
glucagon-like peptide 1 receptor (GLP-1R) is overexpressed in insulinoma
lesions, which is the main cause of AHH. Currently, the PET imaging agent
68Ga-NODAGA-exendin-4 is under investigation as preoperative diagnostic imaging
agent which shows highly specific uptake in insulinoma lesions. Therefore,
GLP-1R is considered to be a promising molecular target for intraoperative
imaging as well. In this feasibility study, we would like to investigate if the
fluorescent tracer exendin-4-800CW is targeting pancreatic beta cells for
future optimization of surgery in patients with AHH.

The primary objective is to determine if accumulation of the fluorescent tracer
Exendin-800CW can be detected to identify beta cells in patients undergoing
pancreatic resection. Secondary objectives are to identify the dose of the NIR
peptide (Exendin-4) conjugate that provides the best visualization of beta
cells and to obtain information on safety aspects of the tracer.

The current study is a non-randomized, non-blinded, prospective, single center
pilot study. A total of 9 patients undergoing a pancreatic head or tail
resection will be included. The trial will consist of 3 subject cohorts of 3
patients each. The doses for each consecutive cohort will increase from 7 µg to
14 µg and 30µg of the tracer Exendin-800CW. The tracer will be injected 24
hours prior to surgery. Following injection of the tracer all patients will be
monitored at least 2 hours for side effects like nausea, vomiting, headache,
dizziness and hypoglycemia for safety, even though side effects are not
expected. To adequately monitor glucose levels, finger pricks will be performed
just before injection and 15, 30, 60 and 120 minutes after injection of the
tracer. Blood will be drawn at 1, 2, 4 and 24 hours after injection to asses
pharmacokinetic data. After surgery, all patients will be monitored for at
least 14 days. After every three subjects the next dose level cohort opens if
safety outcomes (in terms of (S)AEs) with its following conclusions reveal that
continuation to the following cohort is justified. A total of three cohorts
will be included; therefore, the number of subjects will be 9.

A total of 9 patients will receive an injection of Exendin-800CW 24 hours
before surgery. Directly after surgery the pancreatic tissue will be examined
on the back-table and by image-guided pathology to identify fluorescent
signals.

Time investment for study participants
Patients who are scheduled to undergo a pancreatectomy due to an insulinoma,
another type of neuro-endocrine tumour or because of a suspected
(adeno-)carcinoma are asked to participate in this trial. Once written informed
consent is obtained the patient will receive the tracer 24 hours prior to
surgery. No additional study specific visit to the UMCG is necessary.

Risks for study participants
All individuals will undergo physical examination and blood sampling for
standard laboratory parameters. In addition, all patients will undergo the
current standard preoperative care. Exendin-800CW will be administered 24 hours
prior to surgery. Blood pressure and blood glucose levels will be measured just
before and 15, 30, 60 and 120 minutes after injection of the tracer. Injection
of the tracer may result in nausea and headache as has been reported for doses
10-100µg of Byetta® in therapy studies. In addition, a decrease of blood
glucose levels (0.8 * 2.1 mmol/l has been described after injection of 8 * 14
µg 111In-DTPA-exendin-4 in patients with AHH (Christ E. et al. Lancet Diabetes
Endocrinol 2013;1:115-22). Importantly, regular monitoring of glucose
concentrations injection led to no serious episodes of hypoglycaemia.
Therefore, no side-effects are anticipated with injection of Exendin-800CW,
although patients will be closely monitored. Furthermore, a prophylactic
glucose infusion (5% glucose for 2 hours at 250 ml/h) will be started 15
minutes before injection of Exendin-800CW. Finally, to receive pharmacokinetic
data about the tracer, blood samples will be taken at 1, 2, 4 and 24 hours
after injection. Since the patient receives a prophylactic glucose infusion, it
is possible to draw blood samples from the venous access point created by
placing the infusion line. Therefore, the patient does not have to undergo
multiple venous punctures to draw blood. This leads to less burden for the
patient and reduces the risk of infections.

Benefits for study participants
The addition of the near infrared fluorescence imaging agent does not have
direct benefits for the participating patients. Interference with standard
clinical care is not expected since the surgeons and clinicians are to follow
their normal standard of care.