Multicenter, open-label, controlled, parallel arms clinical study on the performance of SGM-101, a fluorochrome-labeled anti-carcino-embryonic antigen (CEA) monoclonal antibody, for locally advanced or recurrent rectal cancer patients undergoing curative surgery.

In the next decade approximately 5000 patients per year will develop rectal
cancer each year. the treatment of locally advanced and locally recurrent
rectal cancer has evolved from a merely surgical approach to a multimodality
treatment strategy. However, surgery remains the cornerstone of treatment.
Since an incomplete resection (R+) is associated with high local recurrence
rates and diminished disease free and overall survival, achieving a resection
with clear margins (R0) is key. Besides, discriminating between tumor remnant
and fibrotic tissue, caused by neoadjuvant treatment, is often difficult with
preoperative magnetic resonance imaging (MRI) and peroperative visual and
tactile feedback.
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). The hypothesis is that, following preoperative IV
administration of SGM-101 in patients with (recurrent) rectal cancer, 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.
Near-infrared fluorescence-guided oncologic surgery (FGOS) with the use of a
tumor specific tracer (SGM-101) developed by Surgimab can provide valuable
intra-operative information about tumor location and extensiveness, which can
be difficult to detect with conventional visual and tactile feedback. Hence,
this information could aid in intra-operative decision making and therewith
foster complete resection margins and less extensive surgery. Subsequently,
this may drastically improve patient care by improving oncologic outcome.

This study has been transitioned to CTIS with ID 2024-510768-21-00 check the CTIS register for the current data.

This study aims to investigate if fluorescence guided surgery performed with
SGM-101 can improve R0 resection rates and allows to find additional malignant
tissue in locally advanced and recurrent rectal cancer, or to achieve a
*positive* change in surgical plan or post-surgical management and thereby
improve patient related outcomes.

This is a national phase III, multicenter, open label clinical trial on the
performance of SGM-101, a fluorochrome-labeled anti-carcino-embryonic antigen
(CEA) monoclonal antibody, for the delineation of locally advanced and
recurrent rectal cancer. Patients will be followed for a total duration of two
years postoperatively.

The proposed dose is 10 mg to be administered intravenously over 30 minutes 4
(+/-1) days prior to surgery. During surgery a fluorescence imaging device will
be used to intraoperatively visualize tumor tissue.

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

Based on the 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, suggesting that toxicity associated with its use should be
minimal. Nevertheless, SGM-101 will be administered under the supervision of a
medical doctor with measures to deal with any potential adverse reactions.

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. Exposure
to the excitation light source, e.g., a laser or LED source, will be limited
during the procedure.

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 have without the system.

As proven with extensive knowledge of the Leiden University Medical Center and
Catherina Hospital Eindhoven research team the presence of a camera system in
the operating room is not novel and should create little problem with
maintaining a sterile field. In this case, the camera will be used initially
prior to surgical excision to record the localization of tumors and
post-excision to document the remaining 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 has been no adverse events reported with this system or
similar systems.

While SGM-101 appears to specifically localize in colorectal 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 or pancreas
cancer may not be known before surgery but most patients (>90%) will likely
have CEA expressing tumors.

In this protocol, we propose different steps in order to prevent unnecessary
tissue resection and subsequent potential adverse events. Resections only take
place when both surgically feasible and clinically significant as judged by the
surgeon. Moreover, in case of discordance between clinical inspection and NIR
fluorescence imaging, it will be possible to obtain a frozen section for ad-hoc
histopathology assessment at the discretion of the surgeon.

Despite these precautionary measures, an adverse event caused by unnecessary
tissue resection may still occur. It is important to realize that the potential
adverse reactions from unnecessary tissue resection are no other than
complications expected during standard resections for colorectal cancer.

An unnecessary tissue resection is defined as resection of suspected malignant
tissue (either by white light inspection or near infrared inspection),
confirmed by the pathologist as non-malignant tissue. This makes a necessary
tissue resection: resection of suspected malignant tissue (either by white
light inspection or near infrared inspection), confirmed by the pathologist as
malignant tissue.

Following on these two definitions, an unnecessary resection can occur during
conventional (without SGM-101/NIR inspection) surgery and in our experimental
group. As mentioned above, adverse reactions caused by an unnecessary resection
are the same as adverse reactions from necessary resections. Such as bleeding
(from the wound bed), hollow organ perforation and surgical site infection.

The potential benefits of SGM-101 cancer imaging in colorectal cancer are:
- Improved staging of the tumor;
- Differentiation between tumor and fibrosis allowing prevention of unnecessary
removal of non-tumor tissue
- Removal of more lesions, otherwise invisible to the naked eye;
- Intraoperative detection of irradical resection (margins) and thus allowing
re-resection and adequate application of IORT