Phase I light-dose escalation study in locally advanced pancreatic ductal adenocarcinoma: Intra-arterial (IA) padeliporfin vascular-targeted photodynamic therapy (VTP).

Abstract

TPS4267 Background: Locally advanced pancreatic ductal adenocarcinoma (LA-PDAC) with > 180° vascular encasement of major abdominal arteries is considered unresectable and is associated with poor prognosis. Standard-of-care options, including chemotherapy and chemoradiation, achieve limited conversion to resectability with high recurrence rates. Thus, a therapeutic approach that can effectively downstage LA-PDAC to resection is clinically needed. Activation of vascular-targeted photodynamic therapy (VTP) by Padeliporfin illumination at 753nm results in photochemical generation of oxygen and nitric oxide radicals that cause rapid occlusion followed by break down of the tumor vasculature, tumor necrosis and break-down of the extracellular matrix. Photosensitivity at > 6 hours is avoided due to 1.19 hours Padeliporfin half-life without accumulation in epithelial tissue. Padeliporfin-VTP activation by intra-arterial (IA) illumination has the potential to selectively ablate tumor tissue encasing the artery, reducing vascular encasement and enabling subsequent surgical resection. Robust feasibility and safety preclinical studies in normal swine and efficacy in mouse tumor models have demonstrated feasibility of light transmission through the arterial wall at a dose sufficient to induce tumor ablation at the artery interface and acceptable safety profile, supporting clinical translation. Methods: NCT05919238 is an ongoing multi-center Phase I light dose-escalation study. Key inclusion criteria are stage III LA-PADC with solid tumor contact > 180° in head/uncinate process of the pancreas for the total encasement length up to 3cm and with target artery internal diameter 5-10 mm. VTP is applied via IA placement of an optical fiber, inside a standard angioplasty balloon, in the target artery adjacent to the tumor. Ten minutes intravenous administration of Padeliporfin at a fixed dose of 4 mg/kg immediately followed by 753nm laser illumination through the inflated balloon, for two 5-minute cycles with 1-minute break. The study is designed to evaluate three light power densities: 200, 400 and 600mW/cm. The primary objectives include determination of Maximum Tolerated light Dose (MTD) and/or recommended phase 2 dose (RP2D) and evaluation of safety. Secondary objectives are to determine rate of surgical downstaging and resectability as well as the pattern of disease progression following VTP treatment, based on pre- and post-VTP contrast computed tomography (CT) scans and tissue specimens, in case surgery is performed. The study comprises two parts: part A with 3+3 light dose escalation schema; part B (expansion cohort) with the RP2D/MTD, derived in Part A. As of 28 October 2025, Cohort 1 of Part A with an LPD of 200mW/cm have been completed without DLTs. Enrolment to cohort 2, with LPD 400mW/cm, began in November 2025. Clinical trial information: NCT05919238 .