FLUOPANC-trial - Intraoperative near-infrared fluorescence imaging in pancreatic- and extrahepatic bile duct tumors using cRGD-ZW800-1 and dedicated imaging systems: A phase II feasibility, dose-ranging and optimal dose-(interval) selection trial

Pancreatic cancer is 4th leading cause of cancer death in the United States.
Prognosis is very poor with median survival of < 6 month. Upon diagnosis, the
disease is associated with a 1-year and 5-year survival rate of ~25% and < 5%,
respectively. Surgical resection is the only curative option with a 5-year
survival rate of up to 20-30% depending on the tumor size. However,
discriminating between malignant and benign tissue can be challenging,
especially after neoadjuvant treatment. Currently, enhancing contrast of
structures using near-infrared (NIR) fluorescence is a technique under
development. It can provide accurate and real-time visualization of tumors
during surgery. Fluorescent agents are intravenously administered and
specifically bind to malignant cells or tumor-associated tissue, such as
neoangiogenic vessels or stroma, and emit light in the invisible, near-infrared
spectrum (i.e. 700-900 nm). Using a dedicated fluorescence imaging system,
contrast of tumors relative to their background can be improved, which allows
real-time image-guided surgery and improve complete resection rates.
cRGD-ZW800-1 is a fluorescent contrast agent that specifically binds to
integrins associated with neo-angiogenesis, and has the potential to improve
visualization of pancreatic cancer cells during surgery and therefore
increasing the R0 resection rate.

- To assess the feasibility, safety and tolerability of cRGD-ZW800-1 for
visualization of (neoadjuvantly treated) pancreatic carcinomas, perihilar or
distal cholangiocarcinomas and if present associated metastatic lymph nodes and
their distant metastases using dedicated NIR fluorescence imaging systems.

- To define the optimal dose and dose interval of a single intravenous bolus
injection of cRGD-ZW800-1.

The study was designed as an open-label, phase II clinical trial with a
2-factorial design: A phase II feasibility test, dose and optimal dose
(interval) selection study.

Intervention: Single bolus injection of cRGD-ZW800-1 2-24h before surgery.
Intra-operative in-vivo assessment of NIR-fluorescence of tumor, lymph nodes,
possible distant metastasis and anatomical related structures. After resection
ex-vivo assessment of NIR-fluorescence of all resected tissue, on
gross-macroscopy, bread loafs and microscopic slides.

Investigational drug: Intravenous single bolus injection of the targeted NIR
fluorophore cRGD-ZW800-1. This targeted 800nm zwitterionic fluorophore
developed by the Hospital Pharmacy Department of LUMC consists of the
fluorophore ZW800-1 conjugated to the cRGD peptide.

Imaging: Intraoperative imaging will be performed with at least one of the
following CE-marked near-infrared (NIR) fluorescence imaging systems: Quest
Spectrum imaging platform (v2/3.0) for open-procedures, the Olympus or
Karl-Storz system for the diagnostic laparoscopy or the Intuitive Surgical Da
Vinci Xi (Firefly-mode) for minimally invasive robot-assisted procedures. With
a NIR-imaging system a potential fluorescent signal of the tumor can be
evaluated. Furthermore, the Quest Spectrum platform will also be used for
evaluation of ex-vivo fluorescence of resected tissue on the back table (Back
table imaging) and pathology department (ex-vivo imaging), which shall be
performed during and after every procedure.

Patients participating in this study will undergo intraoperative
NIR-fluorescence imaging after injection of a single bolus solution with the
cRGD-ZW800-1 NIR-fluorophore. NIR-fluorescence imaging is a clinical technology
that requires administration of a fluorescence-imaging agent that can be
excited at near-infrared (NIR) wavelengths of ~800*nm. Upon illuminating tissue
surfaces with penetrating NIR light to excite the imaging agent within the
tissues, the generated fluorescence is collected to form a two-dimensional (2D)
image demarking the tissue deposition of the imaging agent. This study drug
(cRGD-ZW800-1) and study design have been used previously in colorectal cancer
patients (phase II). All study drug administrations will be done in the clinic
under medical supervision. The patients receiving any study drug will remain in
the clinic after the administration of the study drug and subsequent surgery.
Thus, the patients can be closely monitored for any adverse signs during the
different treatments. Therefore, providing the protocol is adhered to, careful
observation and medical management will minimize any associated risk in this
study. Previous clinical phase I-II studies showed no adverse events related to
cRGD-ZW800-1 injection, as well as no significant changes in vital signs, ECG
or laboratory analysis were observed. Although, when administrating an
investigational product, it is possible that unknown side effects or
(hyper)sensitivity reactions occur. Based on experience with other fluorescent
tracers, such reactions are generally mild and transient in nature. The risk of
damage in this study related to administration of this compound is considered
negligible.

The scheduled (partial) pancreatic resection will be carried out according to
standardized peri-operative planning, besides white-light visual inspection
(WLI) and palpation, NIR-fluorescence imaging will be performed before and
after resection to additionally to screen and inspect the target lesion, the
vital structures, and four-abdominal quadrants as study procedure. Aiming to
identify, visualize and delineate the primary tumor, related vital structures
in the surgical field and fluorescent positive, white-light occult suspect
tumor(rest) in the surgical bed; in lymph nodes, the peritoneal lining, liver
or abdominal fat. NIR-Fluorescence imaging is an addition on the standard
practice of clinical assessment with white-light visual inspection and
palpation, safety and the clinical assessment will always be leading in the
decision of responsible surgeon(s) to deviate from the initial plan. Concrete,
when the additional NIR-fluorescence imaging results in identification of
suspected (rest-)tumor tissue in the surgical bed (i.e. suspect positive
surgical margins), or identification of suspect lymphoid or distant metastatic
disease, the surgeon*s final decision to perform an additional resection, will
be based on clinical (re)assessment with this additional information. In which
the deviation of the resection, e.g. resection of additional tumor-suspect
(pancreatic) tissue in the resection bed or around related structures (veins,
arteries, lymph tracts) or suspect lymph nodes, is always carefully weighed and
only perfumed if considered safe and surgically feasible. Intraoperative
freeze-biopsy(-ies) could be performed to prove presence of malignant tissue
and support intra-operative decision-making.

Thus, participation in this study could result a more accurate intra-operative
assessment of local tumor status, including the identification of suspected
incomplete resection margins in the surgical bed, or identification of suspect
lymphoid or distant metastatic disease. Which will be based on all available
information gained from pre-operative diagnostics, clinical assessment and WLI,
complemented by NIR-fluorescence imaging and the option for
freeze-biopsy(-ies). Furthermore, if additional (suspect) tumor tissue will be
resected, this concerns a minimal amount. In concrete terms, one or a few
nano/millimeters of tissue of the surgical margins or additional lymph nodes
around the tumor. Given the magnitude of the planned surgery, the likelihood of
harm caused by potential tissue removal based on a false positive signal could
be graded nihil. Therefore, the potential harm related to intraoperative
NIR-fluorescence imaging is estimated to be minimal compared to the potential
benefit of a more accurate assessment of local tumor status and the potential
of a more complete (radical) resection of the tumor.