As systemic therapy improves, local control of nonmetastatic pancreatic adenocarcinoma (PDAC) remains a major challenge. Up to 40% of patients present with locally advanced and borderline resectable anatomy, for whom enhanced local downsizing of disease could improve resection rates and thus overall survival (OS). Additionally, for the 20% of PDAC patients who undergo resection, improved postoperative local control may translate into improved local disease-free intervals. Targeted therapies with reduced systemic toxicity are needed for the treatment of PDAC since current therapies have not provided meaningful advances. PanTher is developing a novel locally targeted drug delivery product (PTM-101) to treat localized PDAC by directly delivering chemotherapeutic agents to the primary tumor. PTM-101 is a bioresorbable polymeric patch containing paclitaxel surgically placed onto the tumor. The ingredients biodegrade over time, resulting in sustained release of drug, thereby providing localized treatment. In murine orthotopic patient-derived xenograft models, we showed that PTM-101 is 12 times more effective in controlling tumor progression compared to the same agent given via systemic route, without the toxicity of systemic therapy. In addition, increase in OS and inhibition of metastasis have been achieved after single treatment. Here we describe testing the implantation of clinically sized product in large animal models in preparation of our first-in-man study. To understand feasibility and safety of implant of PTM-101, two pilot studies were conducted in porcine models. In the first study, PTM-101 was sterilely implanted onto the peritoneum laparoscopically. In the second, it was placed in an open technique directly onto the ventral surface of a healthy porcine pancreas. In both cases, PTM-101 was designed to deliver drug locally over a 30-day period. Study parameters included body weights, hematology, urinalyses, drug levels in the blood and at the implantation site, and histomorphologic evaluation of major organs. In these models, we demonstrated that surgical implantation of PTM-101 can be achieved without complication and our approach ensures localized delivery of a large amount of encapsulated drug, resulting in higher drug concentration and retention in the area underneath the implant. More importantly, no detectable levels of the drug were present in the blood at any point during the 30-day treatment, validating once more the ability of PTM-101 to direct delivery only at the intended site. By changing the route of administration to target just the area of interest, PTM-101 is designed to 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 patients with localized PDAC: (i) preoperatively 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.
Citation Format: Margaret Lashof-Sullivan, Amanda L. McSweeney, David T. Ting, Michael P. Kim, Ching-Wei D. Tzeng, Laura Indolfi. Targeted and sustained drug delivery therapy for localized pancreatic cancer: In vivo validation in porcine models [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr B26.