Multicentrum, semi-blind, gerandomiseerde, gecontroleerde, parallelle armen, klinische studie naar de werking van SGM-101, een fluorochroom-gelabeld anti-carcino-embryonaal antigen (CEA) monoklonaal antilichaam, voor de afbakening van primaire en recidiverende tumor en metastasen bij patiënten die curatieve operatie ondergaan voor colorectale kanker.

Technological advances have been made in cancer diagnostics and therapeutics
during the last years
to compensate for the high rate of death due to cancer over the world. Although
modern surgical
advancements have improved surgical oncology, adequate tumor visualization
remains a limitation
preventing total removal of cancer tissue. Surgeons rely primarily on white
light reflectance, which
limits the differentiation between healthy tissue and tumor and can lead to
residual cancer cells
inadvertently left behind [1]. Oncologic surgeons agree that advances in
fluorescence imaging using
targeted probes to enhance the visual capability of the operating surgeon
beyond that of white-light
reflectance would provide a major opportunity to improve outcomes [2]. The goal
of administration
of SGM-101 is to provide oncologic surgeons with an intraoperative imaging tool
that will offer them
pseudo-color distinction between tumor and adjacent normal tissue thus allowing
them to visualize
and delineate tumors overexpressing CEA, particularly colorectal tumors and
their metastases.

The primary objective of this clinical trial is to assess the performance of
SGM-101 in the
intraoperative detection of resection margins and metastases in patients
undergoing curative
surgery for colorectal cancer. SGM-101 will be administered as a single
intravenous dose, at the
optimal dose and according to the schedule determined in the Phase I/II
studies.

This is a randomized, multicenter, semi-blinded parallel-group, Phase III study
on the performance of
SGM-101, a fluorochrome-labeled anti-carcino-embryonic antigen (CEA) monoclonal
antibody, for
the delineation of primary tumor, recurrent disease and metastases in patients
undergoing curative
surgery for colorectal cancer.
The focus of this trial is on the evidence needed for an indication of improved
visualization based on
the concordance between histopathology and tissue fluorescence. The control is
standard operating
conditions or what can be called white light surgery, and each patient in the
SGM-101 arm is his own
control. Indeed surgeons will have the possibility to turn the near-infrared
camera on and off when
they need during the procedure, several times if necessary. Moreover there is
no possibility to blind
the surgeons in such an imaging procedure as they will know immediately if the
patient has received
SGM-101 when turning-on the near-infrared light.
300 patients will be randomized with an unbalanced randomization ratio of 4:1
(SGM-101 guided
surgery: saline injection and standard surgical treatment). The randomization
will be stratified
according to two stratification variables:
• tumor location-and-type with the following five categories:
o cT4 colon cancer
o cT3/4 rectal cancer
o recurrent colon cancer
o recurrent rectal cancer
o peritoneal metastasized colorectal cancer
• geographical region with two categories
o USA
o Europe.
The objective of the control arm is to assess the influence of the fluorescence
on the surgical
approach and thus on the safety of each patient. Indeed, for clear ethical
reasons, no surgeon shall
deliberately minimize the initial resection knowing that the SGM-101
fluorescence would constitute
a back-up security on visible defects. Nor shall he be more aggressive in the
presence of
fluorescence. There will be very clear instructions to follow standard of care
tumor assessment (that
has to be done in white light at the beginning of every surgical intervention).
In the SGM-101 arm
the surgeons will have the possibility to assess the presence of additional
tumor lesions by use of
fluorescence but in no case shall they modify their initial global evaluation
routine. Documentation
of patients* short-term outcome in both arms shall give sufficient information
on a possible
surgeons* bias to use an overly-aggressive approach (too much resection) caused
by fluorescence.

Eligible and consenting patients will be randomized 4:1 to one of two groups (A and B). • Group A: SGM-101 injection followed by conventional then fluorescence tumor assessment. • Group B: Saline injection followed by standard surgical treatment - conventional tumor assessment SGM-101 is a CEA-specific chimeric antibody conjugated with a NIR emitting fluorochrome, developed as an intraoperative imaging agent for the delineation and/or detection of tumors. The SGM-101 active ingredient is a covalent conjugate of the SGM-Ch511 anti-CEA chimeric monoclonal antibody with the fluorochrome BM-104 (Figure 1). The BM-104 fluorochrome is conjugated to free amino groups of the antibody via a stable heterobifunctional linker and an amide bond.

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;
• Adverse events resulting from unnecessary tissue resection.
To maintain a sterile field, the camera will be used initially prior to
surgical excision to record the
localization of tumors and post-excision to document the status and does not
interfere with sterility
requirements. Standard hospital procedures to ensure sterilization or masking
of the equipment will
be employed.
There is a potential for phototoxicity from any light source. The degree of
risk is related to the power
of the beam and the extent of exposure. Controls will be in place to ensure
exposure is limited to
what is necessary to capture the images needed.
While SGM-101 appears to specifically localize to colorectal carcinomas, there
is a possibility that
some patients will have CEA-negative tumors and will not benefit from the use
of this agent. The CEA
expression of CRC may not be known before surgery but most patients (>90%) will
have CEA
expressing tumors. In the case where the tumor would not express CEA, SGM-101
would be
eliminated with no risk for the patient.
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 resulting in altered binding.