Intraoperative detection of tumor tissue in pancreatic cancer using a VEGF-targeted optical fluorescent imaging tracer

De prognosis for patients with pancreatic cancer is poor. The combination of
pre- and intraoperative limitations in staging results in 50%-75% positive
margin rates (tumor < 1mm of the resection margin, R1 resection)) in standard
of care for surgery with curative intent (4-6,38). Therefore, they need a
technology that intraoperatively detects tumor affected tissue accurately and
reliably in PDAC. There is a need for better visualization of resection margins
and detection of small tumor deposits during surgery for pancreatic cancer.
Optical molecular imaging of pancreatic ductal adenocarcinoma associated
biomarkers is a promising technique to accommodate this need. The biomarker
Vascular Endothelial Growth Factor (VEGF-A) is overexpressed in pancreatic
cancer tissue versus normal tissue and has proven to be a valid target for
molecular imaging. We hypothesize that bevacizumab-800CW accumulates in VEGF
expressing cancer, enabling pancreatic cancer visualization using a NIR
intraoperative camera system. We want to test this hypothesis in this pilot
intervention study and furthermore we will determine the optimal dosage of
bevacizumab- 800CW dosage (4,5 10, 25 or 50mg) to detect pancreatic cancer
tissue intraoperatively.

Part 1
1. Determine if accumulation of the fluorescent tracer bevacizumab-800CW can be
detected for identification of pancreatic cancer tissue during surgery.
2. Identify two doses of conjugate that provide the best visualization of tumor
tissue during surgery.
3. To obtain information on safety aspects of the tracer, side effects, adverse
events (AE), serious adverse events (SAE) and suspected unexpected serious
adverse reactions (SUSAR).

Part 2*
Define which of the two doses of conjugate identified in part 1 is the optimal
dose for further development in a phase II/III trial

This is an interventional exploratory dose escalation trial to be conducted in
two trial centers. Studying the fluorescence signal in pancreatic cancer tissue
after administration Bevacizumab-800CW 1:2 conjugate (second generation tracer)
in patients with clinical suspicion of pancreatic head cancer who are scheduled
to undergo surgical intervention with curative intent. The main objective of
this study is to determine if accumulation of the fluorescent tracer
bevacizumab-800CW can be detected for the identification of pancreatic cancer
tissue during surgery. The secondary objective is to define the optimal dose of
the tracer for the visualization of intra operative tumor delineation. For this
purpose the study will comprise of 2 parts. In part 1 small cohorts of 3
patients will receive increasing doses of the tracer: 4,5, 10, 25 and 50 mg
subsequently. After completion of each cohort efficacy data will be reviewed by
determining the fluorescent signal and safety reports. A DSMB is involved to
monitor safety and provide advice if the study can proceed to he next dose. In
part 1 the two doses with optimal performance will be defined. In part 2 the
sample size for the two optimal doses in part 1 will be increased to 10
patients for each of the two dose groups, which is thought to be a sufficient
sample size providing a good conclusion with regards to the dose of the tracer
that is to be used for further development in a phase III trial.

In part one a maximum of 12 patients will receive a single bolus injection of
Bevacizumab-800CW three days before surgery. During surgery seven imaging
moments are defined in which the near infrared intraoperative camera system
will detect the fluorescent signal. The two most optimal dosages will be
identified by determining the fluorescent signals. In part two will these two
cohorts be extended to ten patients each to define which of the two doses is
the optimal dose for further development in a phase II/III trial

Risks to study participants are mainly related to the administration of the
tracer in increasing dosages. A data safety monitoring board (DSMB) will be
installed to carefully monitor safety issues and is authorized to stop the
study at any time. Although no specific safety concerns have been raised for
the Bevacizumab-800CW conjugate the researches will take into account a
possible safety issue which was reported for the Cetuximab-conjugate. A
persisting but transient prolongation of QTc was observed in an animal toxicity
study (29) and also in the human dose escalation study performed by prof. E.
rosenthal. Prof. E. Rosenthal concluded that these side effects were most
likely attributable to simultaneous observations of hypomagnesemia,
hypocalcemia and hypokalemia which are known side effects of Cetuximab.

The surgical procedure for removal of pancreatic cancer is a very extensive
procedure with a high risk of complications. In prior research in the UMCG
30-day mortality rate was 4% (7/176) in patients who underwent a resection. The
median intensive care unit stay was 1 day (range 0*73) and median total
hospital stay was 24 days (range 9 *131). In the patients who underwent a
resection, 29.5% (52/176) had one or more general complications, and 34.1% had
a procedure-related complications. 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 160 mg 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 recorded {Starlinger:2012hv}. Since the Bevacizumab-800CW will be
used in a dose far below 160mg will therefore cause no additional complication
risk.