Novel targeted and sustained drug delivery therapy for localized pancreatic cancer: Validation in porcine models and minimally invasive surgical feasibility in human cadavers.

Abstract

e16747 Background: As systemic therapy improves, control of localized pancreatic adenocarcinoma (PDAC) remains a major challenge. Up to 40% of patients present with locally advanced and borderline resectable tumors, for whom enhanced local downsizing of disease could improve resection rates and survival. PanTher is developing a locally targeted drug delivery product (PTM-101) to treat localized PDAC by directly delivering chemotherapy to the primary tumor. PTM-101 is a bioresorbable polymeric patch containing paclitaxel surgically placed onto the tumor. It biodegrades, resulting in sustained localized release of drug. In murine orthotopic patient-derived xenograft models a 60% increase in OS and inhibition of metastasis was achieved after single treatment. Here we validate and de-risk PTM-101 implantation in standard OR settings in large animals and human cadavers to prepare for a phase 1 study. Methods: We conducted two 30-day studies in porcine models to assess safety, toxicity and biodistribution. Parameters included body weights, hematology, urinalyses, drug levels in the blood and at the implantation site and histomorphologic evaluation. To validate the feasibility of minimally invasive surgical insertion, we conducted a follow-up study in three human cadavers. In each case, PTM-101 was laparoscopically placed directly on the pancreas. Results: We surgically implanted PTM-101 without complications and our approach ensures localized drug delivery with extreme control of drug biodistribution. Importantly, no detectable levels of drug were present in the blood any time during the 30-day treatment, confirming our targeted delivery. PTM-101 was consistently and effectively placed during a minimally invasive surgery without substantial increase in procedure time. PTM-101 conforms fully to pancreatic tissue, allowing for close contact with the intended tissue for drug delivery, and can cover the areas of the pancreas where critical involvements of tumors with vasculature are commonly found. Conclusions: By changing the route of administration to target just the area of interest, PTM-101 can increase the amount of drug reaching the tumor with the aim to enhance therapeutic efficacy. This could open the door to clinically relevant applications in PDAC patients: (i)pre-operatively as neoadjuvant treatment to control progression and downsize locally advanced and borderline anatomy to improve resectability; or (ii)post-resection to reduce the rate of local recurrence.