Development of a fluorescence labelled agent for the detection of pre-cancerous lesions in the colon.

Colorectal cancer is one of the major causes of death globally and morbidity, mortality and healthcare costs can be vastly reduced if the disease can be detected more accurately at an early stage. Colonoscopy is a highly accurate test for detecting and d iagnosing colorectal cancer. However, detection of so-called flat lesions and discrimination between pre-malignant and benign lesions is not possible with standard white light endoscopy. Our own R&D has identified a peptide with a high affinity for a targ et that is overexpressed in early colon cancer. The peptide will be coupled with a fluorescent dye and a formulation for intravenous use will be developed. Preclinical safety studies will be performed to study the safety of the agent. Imaging of the age nt GE-137 will require development of a specialized colonoscope. The colonoscope must be designed to perform high sensitivity fluorescence imaging in the far red part of the spectrum. The colonoscope must also be able to perform white light reflective ima ging. The current strategy is to first implement a prototype system for Proof of Concept (PoC) and Phase 1 clinical trials that satisfies the criteria for these studies, and which can be implemented in the required time frame. The performance will need to be validated and quantified by a rigorous acceptance testing procedure. SINTEF has been identified as an expert partner to perform this work. Methods for clinical use and workflow procedures are new, with little or no precedent, and will need to be dev eloped. An anatomically relevant phantom of the colon, with appropriate optical properties and fluorescence intensity is required for development and validation of the proof of concept clinical study protocol. Endret 02.02.12: There have been changes fro m the original project plan. 1) Development of the colonoscope and phantoms was more complicated and took longer than anticipated. 2) The phase 1 study was performed in the Netherlands instead of USA; this change had no impact on timelines. 3) As validati on data for the colonoscope were needed for the IMPD, the delay in developing the scope delayed submission of the IMPD for the phase 1 study. 4) Approval of the IMPD took slightly longer than expected. 5) Enrolment of subjects in the phase 1 study took lo nger than planned. 6) Development of the immunohistochemistry-based method for semi-quantification of the molecular target for GE-137 in tissue samples collected from enrolled subjects was severely delayed due to technical difficulties. 7) The number of l esions observed in the 15 subjects at high risk of CRC was much higher than expected. Therefore, the high total number of samples collected (from normal mucosa and polyps) during the study has resulted in the evaluation process being more time consuming t han originally estimated. It was anticipated that a phase 2 PoC study could be initiated in 2011. Due to the delays mentioned above, this was not possible. However, data from the 101 lesions (areas of increased fluorescence and/or areas scored in white li ght as suspicious based on morphology) that were detected and sampled in the 15 subjects at high risk of CRC will likely give a good initial indication of PoC. However, at this point in time, not all data have been processed, despite best efforts. Current ly, 70% of collected tissue samples have been scored for expression of the molecular target for GE-137, and the remaining data are expected in December 2011. Data analysis will be carried out in the first quarter of 2012, and the results will be reported and published. The data analysis and reporting activities will require significant resources. Since this work cannot be performed in 2011, the Project Owner requests extension of the original contract period by 3 months, to 31st March 2012, in order to co mplete it. However, because a number of activities enabling start of the PoC study were not started, total overall costs versus those envisaged in the original plan are substantially reduced.