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. Despite advances in surgical and systemic treatment, the 5-year overall survival (OS) rate remains approximately 10%. This low survival rate is mostly caused by late detection of disease due to the late onset of symptoms. 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). 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.

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. 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. As a consequence, vascular tumor involvement is often overestimated and also hard to interpret with substantial interobserver variability. 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.

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. 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.

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). 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. 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. From a previous study conducted in the LUMC with this compound in patients with (borderline) resectable pancreatic cancer the investigators 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. 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, CEA expression on the targeted PDAC tissue is expected to be none to minimally influenced by the neoadjuvant treatment, either FOLFIRINOX or a combination of Gemcitabine with or without radiotherapy, as described by previous studies. 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%). Moreover, an expansion on this study 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 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.

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.