Fluorescence guided surgery for intra-operative detection of meningioma using Bevacizumab-IRDye800CW

Meningiomas are the most frequently occurring brain tumors in adults,
accounting for one third of all cases. In the last decades, treatment of
meningiomas has mainly remained unchanged. Surgical treatment of newly
diagnosed meningiomas has a curative intent and aims for both complete tumor
resection and preservation of neurological function. Neurosurgeons depend on
visual inspection to distinguish tumor tissue from healthy surrounding brain
tissue. Unfortunately, the human eye is not competent enough to detect
molecular changes in intracranial lesions that have the same color and
structure, or to distinguish tumor lesions from benign scare tissue originating
from a previous surgery. This is the major cause of tumor recurrence/regrowth.
Currently, differentiation between meningioma tumor invasion in the dura mater
or adjacent bone and reactive tissue is limited.

MFGS, a promising imaging technique for real-time intraoperative tumor
detection by using a tumor-targeted fluorescence tracer, could serve as a *red-
flag* imaging technique to assist in optimal tumor identification. In the UMCG,
we have extensive experience with fluorescence imaging, using
Bevacizumab-IRDye800CW in both preclinical and clinical setting.

In the present study, we aim to perform a feasibility study with
Bevacizumab-IRDye800CW in patients with meningioma who are scheduled for
elective surgical resection. The ability of fluorescence imaging to identify
residual meningioma tissue that is missed by visual inspection may have the
potential to obtain the goal of complete, safe resection in the future.
Patients with complete resection (Simpson grade I) have decreased morbidity and
mortality, and lower recurrence rates, compared with incompletely resected
meningioma patients.

Data from this trial may be used to design further studies regarding
intraoperative fluorescence detection of residual tissue in meningioma in a
sufficiently powered final multicenter diagnostic accuracy study.

This trial is a non-randomized, non-blinded, prospective single-center phase
I/II feasibility study to be carried out at the UMCG. A maximum number of 19
patients will be included.

The first part of the study will consist of a dose escalation scheme with three
cohorts (4.5 mg, 10 mg and 25 mg Bevacizumab-IRDye800CW) of three patients
each. We will start with a dosage group of 4.5 mg (n=3), followed by dosages of
10 mg (n=3) and 25 mg (n=3). After all three dosage groups have been completed
(total n=9), we will evaluate the safety profile and whether the tumor can be
distinguished from background tissue based on qualitative fluorescence imaging
ex vivo. Background tissue will be defined as the tissue next to the tumor. The
TBR will be calculated by dividing tumor fluorescence by surrounding tissue
fluorescence.

For the dosing cohort, we will select either the best group, or the two best
groups of the dose escalation scheme, depending on the differences between the
three cohorts at the moment of interim analysis. When a single group is
selected, that cohort will be extended to 10 patients (thus including 16
patients in total in this study). When the two best groups are selected, these
will first be expanded to six patients each, after which four patients will be
additionally included in the best group (thus including 19 patients in total).
The data from the group with a total of 10 patients will be used to perform a
power size calculation for future diagnostic accuracy studies. An overview of
the dose escalation scheme is displayed in figure 3.

The study will be terminated if, after the interim analysis of the first nine
evaluable patients, no uptake of Bevacizumab-IRdye800CW in tumor tissue can be
shown by fluorescence imaging or an inadequate TBR is determined.

Patients will receive an intravenous dose of the fluorescent tracer (max 25 mg
Bevacizumab-IRDye800CW) two to four days prior to the surgical resection at the
UMCG. After an observation period of one hour directly after tracer injection,
the patient can go home. The surgeries will be performed as standard of care by
a neurosurgeon. Additionally, fluorescence will be detected intra-operatively
using two fluorescence camera systems (Yoda and Zeiss Pentero) and it will be
quantified using spectroscopy. This will add 30 minutes to the operation time.

Time investment
To decrease the burden of study procedures, we will aim to plan the surgical
resection on a Monday or Tuesday. Thereby, the tracer administration and
admission to hospital will coincide on Friday.

Risks
The administration risks of Bevacizumab-IRDye800CW are reported in the IMPD. No
adverse events have been reported from previous administrations with the tracer
in more than 200 patients. Patients will be observed for one hour after tracer
administration. A crash-car with adrenalin, tavegil and prednison will be
available. The intravenous injection and the use of a cannula are known to
carry a small risk of infection and hematoma. Due to fluorescence imaging,
operation time will be extended with 30 minutes. Risks of imaging are
comparable to standard of care with the Zeiss Pentero.

Benefit
There is no direct diagnostic or treatment benefit for the patients, as all
procedures are processed following standard clinical guidance. No decisions
according to clinical care will be based on study results.