A performance study of SGM-101, a fluorochrome-labeled anti-carcinoembryonic antigen monoclonal antibody for fluorescence-guided imaging to determine local extent and resectability during surgical resection of pancreatic ductal adenocarcinoma after neoadjuvant treatment

Pancreatic cancer is a lethal cancer type and is continuously rising as cause
of cancer-related death in the Western World.1,2 Despite advances in surgical
and systemic treatment, the 5-year overall survival (OS) rate remains
approximately 10%.3 This low survival rate is mostly caused by late detection
of disease due to the late onset of symptoms.4 Therefore, most patients are
diagnosed with advanced stage disease: at the time of diagnosis, about 15% of
patients has (borderline) resectable ((B)RPC) disease (stage I or II), 35%
locally advanced pancreatic cancer (LAPC, stage III), and 50% metastatic
disease (stage IV).5 The resectability of disease is determined by the extent
of tumor contact with the superior mesenteric artery, celiac artery, superior
mesenteric vein, and portal vein.6,7

Over the last decade, preoperative chemo(radio)therapy has increasingly been
used in an attempt to downstage BRPC or LAPC and select patients with more
favorable tumor biology for resection, with the aim to reduce the chance for
(early) recurrence.8 In essence, only patients showing regression or stable
disease without suspected metastatic disease are considered for surgical
exploration. However, preoperative therapy complicates the preoperative
radiological staging, because conventional imaging modalities cannot
differentiate between vital tumor tissue, inflammation and fibrosis induced by
the preoperative chemo(radio)therapy.9 As a consequence, vascular tumor
involvement is often overestimated and also hard to interpret with substantial
interobserver variability.10-14 Therefore, non-progressive disease following
preoperative therapy regarding imaging and tumor markers is usually an
indication for surgical exploration to determine whether radical resection is
achievable.3,4

During surgical exploration preceding intended tumor resection, the surgeon has
to assess the extent of local (vascular) tumor involvement based on
preoperative imaging and visual and tactile senses. This visual intraoperative
White Light Inspection (WLI) combined with tactile feedback, are the main
instruments for guidance and decision-making available to surgeons nowadays. As
a result of neoadjuvant therapy the appearance, dimensions, and tactile
feedback of the target lesion can be altered, mostly as a result of
therapy-induced fibrosis, which complicates the assessment of (local)
invasiveness. Surgeons benefit from additional tools that give them real-time
directional feedback on local tumor status, which is one of the strengths of
optical molecular imaging techniques, like Near-infrared fluorescence (NIRF)
imaging. Near-infrared fluorescence (NIRF) imaging is an emerging important
intraoperative tool for enhancement of visual contrast and is able to provide
real-time guidance in tumor visualization and demarcation.15 Particularly the
use of tumor-specific markers coupled to fluorescent imaging moieties show
great promise to improve intraoperative staging and allow more radical
cytoreductive surgery if considered resectable.16

The compound that will be studied in this trial is SGM-101, a CEA-specific
chimeric antibody conjugated with a NIR emitting moiety developed by SurgiMab
(Montpellier, France).17,18 Anti-CEA monoclonal antibodies have been used in
more than 100 clinical studies without any toxicity concerns. In addition, it
has been shown that it is possible to link an anti-CEA monoclonal antibody to a
near-infrared (NIR) emitting fluorophore. Carcinoembryonic antigen (CEA) is a
tumor-specific marker that is highly expressed in a number of tumors of
epithelial origin (such as colorectal carcinoma and pancreas carcinoma) while
it is minimally expressed in normal adult tissues.19,20 CEA, among others like
Carbohydrate Antigen 19-9 (CA 19-9) is used as diagnostic and prognostic marker
during different stages of malignant pancreatic disease.21 From a previous
study conducted in the LUMC with this compound in patients with (borderline)
resectable pancreatic cancer we learned that near-infrared fluorescence imaging
of pancreatic tumors using a single dose up to 10mg of the anti-CEA targeted
fluorophore SGM-101 is safe, well-tolerated, feasible and effective.22 It
results in specific accumulation of SGM-101 in CEA-expressing primary tumors,
peritoneal and liver metastases, allowing real-time identification and guidance
using intraoperative fluorescence imaging. Furthermore, an additional important
fact for this specific study is that CEA-expression is not altered by
neoadjuvant chemotherapy, as described by Vuijk et al.9 In addition to
experience in pancreatic tumors, there is ample experience from finalized
phase-II and ongoing phase-III studies in patient with colorectal carcinoma. 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%).23 Moreover, an expansion on this study showed no SGM-101
related adverse events up to 15 milligrams in 75 patients.24 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 were 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.23,24

This study has been transitioned to CTIS with ID 2023-510481-27-00 check the CTIS register for the current data.

This study evaluates the yield of NIR-Fluorescence imaging as additional
surgical-tool for visualization and assessment of local extent and
resectability status of neoadjuvant treated localized pancreatic tumors, local
lymph node-involvement as well as potential distant metastatic disease using a
single intravenous dose of 10mg SGM-101.

This is a single-center prospective clinical cohort study in patients with
neoadjuvant treated non-primarily resectable (borderline resectable and locally
advanced) pancreatic cancer undergoing scheduled surgical resection. A total of
48 patients (Part A 24, Part B 24 (healthy volunteers) will be prospectively
enrolled in this study evaluating the performance of NIR-Fluorescence imaging
as an additional surgical-tool for the visualization and determination of the
local extent of primary tumor, lymph node-involvement and occult hepatic and
peritoneal metastatic disease in patients using a single dose of 10mg of
SGM-101. The selected dose is based on the pre-clinical and phase I/II results
in patients with pancreatic and colorectal cancer.

Intervention: single intravenous administration of SGM-101 3-5 days before
surgery. Intra-operative in-vivo assessment of NIR fluorescence of tumour,
lymph nodes, possible distant metastases and anatomically related structures.
After resection ex-vivo assessment of NIR fluorescence of all resected tissue,
on gross macroscopy, bread-loafs and microscopic slides. Additionally, as
exploratory objective, during and after surgery blood samples will be taken to
evaluate te concentration of SGM-101 labeled extracellular vesicles and
quantification of circulating tissue macrophages (TiMa's).

Investigational drug: Intravenous single bolus injection of the targeted NIR
fluorophore SGM-101. This fluorophore consists of the fluorophore ZW800-1
conjugated to anti-CEA antibody

Imaging: Intraoperative imaging will be performed using a CE-marked
near-infrared (NIR) fluorescence imaging system: Quest Spectrum imaging
platform (v2/3.0) for open procedures. With an NIR imaging system, a
fluorescent signal of the tumour can be evaluated. In addition, the Quest
Spectrum platform will also be used to evaluate ex-vivo fluorescence of
resected tissue on the back table (back table imaging) and pathology department
(ex-vivo imaging), which will be performed during and after each procedure.

Patients participating in this study will undergo intraoperative
NIR-fluorescence imaging after injection of a single bolus solution with the
SGM-101 NIR-fluorophore 3-5 days before their planned surgery. In total
participants have to commit to an additional visit to the hospital
(approximately 4 hours) for study drug administration, all other study
activities coincide with surgical admission and standard care pathway. All
study drug administrations will be done in the clinic under medical
supervision. The patients receiving the study drug will remain in the clinic
after the administration of the study drug for two hours, and will be
re-admitted the day of surgery. Thus, the patients can be closely monitored for
any adverse signs during the different treatments. Therefore, providing the
protocol is adhered to, careful observation and medical management will
minimize any associated risk in this study. Previous clinical phase II and
ongoing phase III studies showed no serious adverse events related to SGM-101.
Although, when administrating an investigational product, it is possible that
unknown side effects or (hyper)sensitivity reactions occur. Based on experience
with other fluorescent tracers, such reactions are generally mild and transient
in nature.

NIR-fluorescence imaging using the dedicated fluorescence imaging systems have
shown to be capable of safe visualization of NIR-fluorescence signal in
patients with various solid tumors, including pancreatic cancer using
tumor-targeted moieties. The additional risk of using these intraoperative
camera systems for NIR-fluorescence imaging is deemed negligible when
standardized intraoperative procedures for interpretation and decision-making
based on NIR-fluorescence signals are implemented in the work-flow. If
medically justified (safety and potential benefit) and NIR fluorescence imaging
shows additional extent of the lesion in the surgical plane or adjacent lymph
nodes or distant disease which is not visible during initial clinical
assessment and WLI, the surgeon could decide to resect this additional tissue
when it is safe and surgically feasible. Since this fluorescent+ suspect lesion
will be sent to the pathologist separately and will not influence the
pre-operatively planned surgical strategy (e.g., deviate from the planned
surgical resection based on information solely from fluorescence imaging), the
surgical plan for resection will not be altered. Using this principle, the
clinical assessment with WLI remains the golden standard during the
intervention. All perioperative changes in surgical plan or postsurgical
treatment will be recorded on the CRF. Based on this strategy, the patients*
benefit of participation could be an improved intra-operative visualization of
local tumor status and extent, (vascular) resectability and surgical plane
there. Post-operative, additionally to the standard histopathological analyses,
the pathologist will evaluate the additional (FLI+, WLI-) biopsies/tissue that
have been resected separately for presence of malignant tissue. In case,
pathological examination shows that the additionally (FLI+, WLI-) resected
tissue is 'true positive' i.e. tumor+, this could result in an (oncological)
benefit for the patient. In case pathological examination shows that the
additionally (FLI+, WLI-) resected tissue is 'false positive', there will be no
(oncological) benefit. In concrete terms, the additional resected tissue is
minimal compared to the magnitude of the planned surgery, the likelihood of
harm caused by potential tissue removal based on a false positive signal could
be graded minimal. Therefore, the potential harm for the patient is estimated
to be negligible compared to the potential benefit of a more complete removal
of the tumor.