Cholangiocarcinoma detection using an intraOperative
FlUorescence Image Guided Approach with
Bevacizumab-IRDye 800CW

There is a need for better visualization of tumour tissue, lymph nodes and
resection margins during surgery for perihilar cholangiocarcinoma (PHCC).
Optical molecular imaging of PHCC associated biomarkers is a promising
technique to accommodate this need. The biomarkers Vascular Endothelial Growth
Factor (VEGF-A), Epidermal Growth Factor Receptor (EGFR) and c-MET are
overexpressed in PHCC versus normal tissue and are proven to be valid targets
for molecular imaging. Currently, tracers that target these biomarkers are
available for use in clinical studies. In previous studies with other tumour
types, we tested the tracer bevacizumab-IRDye 800CW for the biomarker VEGF-A
with very promising results, therefore we will start with this tracer. We
hypothesize that the tracer bevacizumab-IRDye 800CW accumulates in PHCC tissue,
enabling visualization using a NIR intraoperative camera system and NIR
endoscopy. In this pilot study, we will determine if it is possible to detect
PHCC intraoperatively and by NIR endoscopy using bevacizumab 800CW, and which
tracer dose gives the best target-to-background ratio. The most optimal tracer
dose will be selected for a future phase II trial.

Primairy
To assess whether bevacizumab-800CW allows for intraoperative fluorescence
imaging of perihilar cholangiocarcinoma and what dose provides the best
visualization of tumor tissue by determining the tumor-to-background (TBR)
ratio ex vivo

Secondary
Part 1
1.Determine if accumulation of the fluorescent tracer bevacizumab 800CW can be
detected
for identification of PHCC during surgery.
2.Determine if accumulation of the fluorescent tracer bevacizumab 800CW can be
detected for identification of PHCC during ex vivo endoscopy.

Part 2
Define if the optimal dose of bevacizumab-800CW provides an adequate TBR ratio
for use in a future phase II trial. When TBR is found to be too low for
bevacizumab-800CW in all three dose groups the study will stop. A new pilot
study in patients with hilar cholangiocarcinoma will then be performed with the
promising fluorescent tracers cetuximab-800CW or c-met.

This is an interventional exploratory clinical trial. We will study the
fluorescence signal in PHCC after administration of bevacizumab-IRDye 800CW in
patients with clinical suspicion of PHCC who are scheduled to undergo surgical
intervention.
The primary objective is to assess whether bevacizumab-800CW allows for
intraoperative fluorescence imaging of perihilar cholangiocarcinoma and what
dose provides the best visualization of tumor tissue. The secondary objectives
are to determine if accumulation of the fluorescent tracer bevacizumab 800CW
can be detected for identification of PHCC during surgery and NIR endoscopy.
For this purpose, the study will comprise of two parts. In part 1 three small
cohorts of a maximum of 3 patients per group will doses of the tracer
bevacizumab-IRDye 800CW: 10mg and 25mg subsequently. Depending on the results
we will deescalate or escalate to 4.5mg and 50mg respectively. After completion
of each cohort efficacy data will be reviewed by determining the fluorescent
signal and by calculating the TBR. The dose group with the highest TBR will be
expanded to 6 patients. If two dose groups perform equally well, both groups
will be expanded to 6 patients. For part 2, we will define if the optimal dose
of bevacizumab-800CW provides an adequate TBR ratio for use in a future phase
II trial. If the TBR is too low in all three dose groups, the groups will not
be expanded and the pilot study will stop. At this point we will rerun the
pilot study with the promising tracers cetuximab-800CW or c-Met.

In part one a maximum of 15 patients will receive a single bolus injection of
bevacizumab-800CW three days before surgery. During surgery, several imaging
moments are defined in which the near infrared intraoperative camera system
will detect the fluorescent signal. When resection is completed it will be
determined if it is also possible to detect fluorescent signal from tumour
tissue by ex vivo NIR endoscopy of the bile ducts.

Time investment for study participants
PHCC patients who are scheduled for surgery with curative intent at the UMCG
are asked to participate in this trial. Once written informed consent is
obtained the patient has one study specific visit for administration of the
tracer. In addition to the surgical procedure the study related procedures are
expected to take up to 15 minutes extra as compared to regular practice.

Risk for study participants
Risks to study participants are mainly related to the, already present, risks
of the surgical procedure and to the administration of the tracer. A data
safety monitoring board (DSMB) will not be installed as in more than 110
patients receiving bevacizumab-800CW, no (serious) adverse events were observed.
For patients who are on combination therapy with Bevacizumab for the treatment
of cancer, it is commonly accepted that the patient can safely undergo surgery
6 weeks after termination of the Bevacizumab therapy: i.e. at this time the
anti-angiogenetic effects have diminished sufficiently to assure there is no
increased risk of bleeding or post-operative complications. The through plasma
levels after 6 weeks wash out of the drug equal the peak plasma levels after a
160mg IV dose (communication and calculations by the Hospital Pharmacy and the
department of Medical Oncology at the UMCG). Furthermore, Starlinger et al
investigated that even after a cessation time of 6 weeks bevacizumab is fully
active and blocks circulating and local VEGF at the time of liver resection,
but no increase in perioperative morbidity is recorded1. Since
bevacizumab-800CW will be used in a dose far below 160mg it will therefore
cause no additional complication risk, as also evaluated in more than 110
patients after receiving bevacizumab-800CW.

Benefits for study participants
The addition of the near infrared fluorescent imaging agent and camera system
during PHCC surgery does not have direct benefits for the participating
patients. Interference with standard clinical care is not expected since the
surgeons are to follow their normal standard of care during tumour resection
surgery. If fluorescent signals are detected during surgery in parts that are
not part of the surgical specimen, a maximum of 3 biopsies per fluorescent area
may be taken to confirm ex vivo analyses if the fluorescent signals represent
cancer tissue.