Detection of pituitary neuroendocrine tumor (PitNET) tissue during endoscopic transsphenoidal surgery using Bevacizumab-800CW: a single center feasibility and dose finding study

There is a need for improved visualization of presence and extent of pituitary
neuroendocrine tumor (PitNET) tissue during transsphenoidal surgery (TSS),
especially in tumors invading the cavernous sinus (CS). Optical molecular
imaging of PitNET associated biomarkers is a promising technique to accommodate
this need. Vascular Endothelial Growth Factor (VEGF-A) is overexpressed in
PitNET tissue compared to normal pituitary tissue and has proven to be a valid
target for molecular imaging. Bevacizumab is an antibody that binds VEGF-A. By
conjugating a fluorescent dye to this antibody, the fluorescent tracer molecule
bevacizumab-800CW is created, which binds to VEGF-A. We hypothesize that
bevacizumab-800CW accumulates in PitNET tissue, enabling visualization using a
molecular fluorescence endoscopy system. In this pilot intervention study we
will determine the feasibility of using microdoses (4.5, 10 and 25 mg) of
bevacizumab-800CW to detect PitNET tissue intraoperatively. Ultimately, this
technique could improve diagnostic accuracy, reduce morbidity in patients with
previously unresectable tumors, both preventing unnecessary repeated surgery
and additional treatments (radiotherapy and/or medical therapy), allowing major
improvements in PitNET management.

The primary objective of this study is to determine the feasibility of
intraoperative fluorescence imaging detection of PitNET tissue during TSS using
the VEGF-targeting optical agent bevacizumab-800CW in tumors with a Knosp grade
of 3 or 4.
Secondary objectives are to identify the optimal tracer dose for imaging of
PitNET tissue during TSS for further development in a phase II molecular
fluorescence endoscopy trial, to quantify fluorescence intensity in vivo and ex
vivo with multi-diameter single-fiber reflectance, single-fiber fluorescence
(MDSFR-SFF) spectroscopy, to correlate and validate both the in vivo and ex
vivo measured fluorescence signals with histopathological analysis and
immunohistochemical staining and to assess the (sub)-cellular location of
bevacizumab-800CW by ex vivo fluorescence microscopy.

The study is a non-randomized, non-blinded, prospective, single center, pilot
dose-finding study. Nine to fifteen patients with a PitNET with a Knosp grade
of 3 or 4 will be included. After inclusion of the first three patients in each
dose group, an interim analysis will be performed to determine
tumor-to-background ratios (TBR) by intraoperative fluorescence in vivo
measurements incl. MFDSFR/SFF spectroscopy data and by ex vivo back-table
fluorescence imaging. After the interim analysis, three scenarios are possible.
Optimally, the two most promising groups will be expanded to a total of six
patients. If only one dose group allows for differentiation between tumor area
and surrounding normal tissue, only this dose will be expanded. If none of the
doses show sufficient contract between tumor and normal tissue, the study will
be terminated after the interim analysis. In case of the first scenario,
expansion of two cohorts, a final analysis will be performed to define the
optimal dose, which will represent a balance between the lowest dose and a
clinically usable TBR, sufficient to discriminate between tumorous and
non-tumorous tissue.

Patients will receive a single bolus injection of bevacizumab-800CW (4.5, 10 or
25 mg) two to four days before surgery. During surgery, three imaging moments
are defined in which the fluorescence molecular endoscopy system will detect
the fluorescent signal.

Time investment
Patients with an established diagnosis of PitNET with a Knosp grade of 3 or 4
who are scheduled to undergo TSS 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 15-20 minutes extra compared to
regular practice.

Risks
The administration risks of bevacizumab-800CW are reported in the IMPD (version
5.0, November 2017, section 2.4, page 44). No adverse events were reported from
previous administrations with bevacizumab-800CW in 187 patients. The endoscopic
transsphenoidal procedure for removal of a PitNET is a standard surgical
procedure with low morbidity and mortality. Median total hospital stay is 4 to
5 days. (Serious) adverse events occurring in subjects will be recorded until
14 days after tracer administration.

Benefits
Patients will have no benefit from this study directly. Surgery will be planned
as usual. Interference with standard clinical care is not expected since the
surgeons are to follow their normal standard of care during TSS. During
surgery, no additional biopsies will be taken for the study and no decisions
will be made based on the fluorescence imaging.