A Phase I/II Study Protocol of a Novel Neoadjuvant 'PRaG' Regimen (Radiotherapy, GM-CSF, and Cadonilimab) with AG Chemotherapy to Improve Resectability in Locally Advanced Pancreatic Ductal Adenocarcinoma: The NeoPRAG Study.

ObjectivePancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with a dismal prognosis, largely due to late diagnosis at an unresectable stage. Neoadjuvant therapy aims to downstage tumors to achieve surgical resectability, but efficacy is limited. The immunosuppressive tumor microenvironment (TME) of PDAC renders it resistant to conventional immunotherapy. To evaluate the safety and efficacy of a novel neoadjuvant regimen (the NeoPRAG protocol) for patients with locally PDAC. The primary goal is to determine the regimen's safety in Phase I and the 1-year overall survival rate in Phase II, with the ultimate aim of improving surgical resectability and survival outcomes.MethodsThe NeoPRAG study is a prospective single-center, open-label, Phase I/II clinical trial designed to evaluate a neoadjuvant regimen in patients with locally advanced (borderline resectable or unresectable) PDAC. The treatment strategy combines the "PRaG" concept (hypofractionated Radiotherapy and Granulocyte-Macrophage Colony-Stimulating Factor [GM-CSF]) with dual checkpoint blockade and chemotherapy. The Phase I portion will determine the safety, tolerability, and recommended Phase II dose (RP2D) of the radiotherapy component using a 3 + 3 dose-escalation design. The Phase II portion will assess the preliminary efficacy of the regimen, with the primary endpoint being the 1-year overall survival (OS) rate. Secondary endpoints include objective response rate (ORR), R0 resection rate, progression-free survival (PFS), and a comprehensive panel of translational biomarkers. The study is planned to commence in December 2023. Patient enrollment and follow-up are expected to be completed by November 2026, with final data analysis scheduled for December 2026.ConclusionThe NeoPRAG protocol outlines an innovative, multi-modal strategy that confronts the immunological barriers of pancreatic cancer. It is hypothesized that this combination will synergistically remodel the TME, induce a potent anti-tumor immune response, and ultimately improve the survival landscape for this devastating disease by increasing conversion to resectability.