Background: Currently, no reliable intra-operative tumor detection and margin assessment technologies are available. Fluorescence-guided surgery (FGS) using tumor specific fluorescent imaging agents can improve intra-operative tumor detection. However, a major limitation is the lack of broad tumor applicability due to complex oncogenotypes and histologic phenotypes. A strategy to overcome this challenge is targeting metabolic vulnerabilities that are more ubiquitous and regarded as generic hallmarks of cancer. The extracellular environment of tumors is relatively acidic compared to the immediate surrounding healthy tissue due to aerobic glycolysis, the so-called Warburg effect. ONM-100, a micellar polymer imaging agent labeled with the fluorescent imaging dye Indocyanine Green (ICG), has an exquisitely pH-sensitive binary on/off mechanism. The micelles dissociate in acidic environments causing the unquenching and fluorescent activation of the ICG dye. As most solid cancer types are acidotic, ONM-100 acts as a generic imaging agent targeting a broad range of tumors. This proof of concept, first in-human study, investigates the safety and feasibility of ONM-100 as an intra-operative fluorescent imaging agent in head and neck squamous cell carcinoma (HNSCC).
Methods: In this phase 1 study, the pH-activated fluorescent imaging agent ONM-100 was administered 24±8h prior to surgery in a dose escalation scheme ranging from 0.3 mg/kg to 1.2 mg/kg in groups. Participants with pathological proven HNSCC were included. Blood was drawn up to day 10 to assess safety and pharmacokinetics data. Intra-operative images were collected of the tumor before and after excision and of the wound bed. After excision ex vivo fluorescence images were obtained from the serially sliced specimen and the formalin fixated paraffin embedded tissue blocks. Fluorescence images were correlated with histopathological assessment on Hematoxylin and Eosin (H/E) stained sections.
Results: In this ongoing clinical trial, 15 participants with pathological proven HNSCC were enrolled between March and October 2018. No tracer related (serious) adverse events were observed. A strong and sharply tumor demarcated fluorescent signal was observed in all 15 participants with in- and ex vivo imaging (median Contrast to Noise Ratio 2.76, IQR 1.08), which correlated with areas of tumor involvement on histopathology. HNSCC could be clearly visualized in vivo during surgery in all cases. In addition, in one patient an intra-operatively clinically unnoticed 2 mm small tumor satellite lesion could be detected in the wound bed using fluorescence imaging.
Conclusion: Preliminary results of this ongoing first in-human study with the pH-activated imaging agent ONM-100 shows that administration of ONM-100 is well tolerated and allows fluorescent visualization both in- and ex vivo. Here, we provide the first data that this pH-sensitive optical imaging agent could be used as a generic imaging agent for FGS and margin assessment. Further analysis on microscopic biodistribution of ONM-100 is currently being performed and possibilities for metastatic lymph node detection will be explored. Meanwhile, participants with breast cancer, colorectal and esophageal cancer will be included to further confirm the generic characteristics of ONM-100.