A FEASIBILITY STUDY OF SGM-101, A FLUOROCHROME-LABELED ANTI-CARCINOEMBRYONIC ANTIGEN MONOCLONAL ANTIBODY FOR THE INTRAOPERATIVE DETECTION OF COLORECTAL BRAIN METASTASES

Brain metastasectomy is an important treatment option for brain metastases of
colorectal origin. A microscopic complete resection (R0) is crucial to improve
the overall survival. Unfortunately achieving a R0 resection can be challenging
and is based upon preoperative imaging and intraoperative inspection and
palpation to discriminate between malignant and normal tissue. To aid the
surgeon in discriminating between tumor tissue and normal tissue, real-time
intraoperative imaging techniques are developed. Particularly the use of
tumor-specific markers coupled to fluorescent imaging moieties shows great
promise for improving intraoperative staging and increase the proportion of
radical (R0) resections.
The compound that will be studied in this study is SGM-101, a CEA-specific
chimeric antibody conjugated with a NIR emitting moiety developed by SurgiMab
(Montpellier, France) (1). The hypothesis is that, following preoperative IV
administration of SGM-101 in patients with brain metastases of colorectal
origin, SGM-101 will bind to CEA expressing cancer cells and these cells can
then be visualized with a NIR fluorescence imaging system, thereby increasing
the chance of complete resection and additional resections.
A recent study in colorectal cancer patients showed that additional malignant
lesions were detected and resected using NIR fluorescence imaging in 6 out of
17 patients (35%) (2). Moreover, an expansion on this study (unpublished data)
showed no SGM-101 related adverse events up to 15 milligrams in 75 patients.
There were no trends or clinically relevant changes in vital signs, ECGs or
laboratory parameters reported. Any changes in the laboratory results reported
in the follow-up moments are related to the surgical procedure. Best imaging
results (according to the tumor to background ratio) were achieved with 10
milligrams injected 3 to 5 days prior to surgery.
In order to increase intraoperative tumor visibility we propose a study to
determine the feasibility of SGM-101 for intraoperative imaging of colorectal
brain metastases. Moreover, the safety of SGM-101 will be monitored.

This study has been transitioned to CTIS with ID 2024-510767-30-00 check the CTIS register for the current data.

1. To determine the feasibility of SGM-101 for intraoperative imaging of
colorectal brain metastases
- Concordance between fluorescent signal and tumor status of resected tissue
- Concordance between the fluorescent signal and the resection margin with the
use of neuronavigation
If it appears that the malignantly resected tissue is fluorescent and the tumor
margin based on fluorescence is similar or even more accurate than the tumor
margin based on neuronavigation (calibrated with the preoperative MRI scan),
then the fluorescent agent SGM-101 can be considered feasible for the
intraoperative detection of colorectal brain metastases.
2. To assess the correlation between fluorescent tissue in the resection plane
and observed residual tumor or tumor progression on the routinely performed
postoperative MRI scans.
3. To determine the Tumor-to-background ratio (TBR);
4. To determine the tolerability and safety of SGM-101

This is a feasibility study of patients undergoing surgery for colorectal brain
metastases. The study will consist of a total of 10 patients with brain
metastases in which the feasibility of 10 mg SGM-101 will be explored during
surgery. The selected dose is based on the pre-clinical and phase I/II results.

10 mg intravenous SGM-101 will be administered over 30 minutes 3 to 5 days
prior to surgery.
The imaging system that will be used in the study is a dedicated camera system
from Quest Medical Imaging (QMI); the Quest Spectrum Platform, that is
optimized for measurements in the NIR-spectrum. For this device ample
experience for intra-operative imaging exists at HMC.

The issues of possible concern with the use of the SGM-101 and accompanying
imaging system are:
- Presence of a camera in the operating room;
- Phototoxicity from the light source;
- Nonspecificity of localization;
- Failure to bind to receptors;
- Fading of the chromophore (photobleaching);
- Inability to excite SGM-101 or to record emission;
- Adverse reactions to SGM-101.

As proven with extensive knowledge of the Leiden University Medical Center, the
presence of a camera system in the operating room is not novel and should
create little problem with maintaining a sterile field. Although neurosurgeons
at the Haaglanden Medical Center already have some experience with fluorescence
surgery, trained researchers from the Leiden University Medical Center will
operate the camera themselves. The Quest Spectrum Platform Camera will be used
initially prior to surgical excision to record the localization of tumors and
post-excision to document the status. As such, it needs not be intrusive during
the procedure. Standard hospital procedures to ensure sterilization or masking
of the equipment will be employed.

There is limited potential for phototoxicity from any light source. The degree
of risk is related to the power of the beam and the extent of exposure. The
power of the beam in this study is low and potential phototoxicity is
negligible. There have been no adverse events with this system or similar
systems.

While SGM-101 appears to specifically localize both colorectal and pancreas
carcinomas, there is a possibility that some patients will have CEA-negative
tumors and will not benefit from use of this agent. The CEA expression of
colorectal cancer and in particular of brain metastases may not be known before
surgery but most patients will likely have CEA expressing tumors.
There is no evidence to date of a failure of SGM-101 to bind to CEA in
pre-clinical models, so this remains a theoretical concern. Possible mechanisms
would be competitive antagonism with another ligand or a change in the molecule
or receptor to hinder binding.

Like all chromophores, excitation by appropriate wavelength of light will
result in molecular activation in which a different wavelength of light is
emitted. This is an active process which changes the excitability of the
molecule leading to photobleaching. Since white light contains all wavelengths
of light, extended room light exposure could also lead to bleaching. During
administration of SGM-101, the infusion bag will be wrapped in aluminium foil.
In addition, exposure to excitation light (laser and LED light) will be limited
to necessary exposure to properly perform the study-related handlings and
surgery. Previous research with SGM-101 has shown that limited exposure to
excitation light does not result in decreased fluorescence signal and is
therefore negligible.

The risk that the imaging system will not excite SGM-101 or record an image
after emission is minimal. An external source of SGM-101 can be used to check
that the system is working. In the event of such failure, the surgeon continues
as he/she would without the system.

Based on experience with SGM-101 and other fluorescent probes, it cannot be
excluded that adverse reactions, such as hypersensitivity reactions, may occur.
However as discussed in paragraph 1.1, binding of anti-CEA antibodies to their
target does not trigger the activation of cell signalling pathways and
radiolabelled anti-CEA antibody in over its 9 years of use, did not cause
adverse effects, this suggests that toxicity associated with its use should be
minimal.
Nevertheless SGM-101 will be administered under medical supervision of a
medical doctor at the LUMC with measures to deal with any potential adverse
reactions.

The potential benefits of SGM-101 cancer imaging in brain metastases of
colorectal origin are:
- Lesion removal with greater precision;
- Intraoperative detection of irradical resection (margins).