Phase Ib study testing neoadjuvant transforming growth factor (TGF)-β antibody, NIS793, plus 5-fluorouracil, irinotecan, and oxaliplatin chemotherapy (FOLFIRINOX) in patients (pts) with borderline resectable (BR)/locally advanced (LA) pancreatic ductal adenocarcinoma (PDAC).
Authors: Weekes Colin D. , Ting David Tsai , Parikh Aparna Raj , Ittershagen Stacie , Fabre Claire , Cremasco Viviana , Ruddy David , Liss Andrew , O'Shea Aileen , Harisinghani Mukesh , Piquet Michelle , Chang Jonathan , Kwak Eunice Lee , Ryan David P. 
Published: January 2023

TPS762

Background: Overcoming resistance to chemotherapy and immune checkpoint inhibitors remains an unmet need for PDAC. In this context, TGF-β plays a key role in PDAC by promoting the activation of fibroblasts and extracellular matrix deposition, facilitating epithelial-to-mesenchymal transition, immune evasion, and resistance to chemotherapy. Combination of FOLFIRINOX with losartan, an indirect TGF-β inhibitor with antifibrotic properties, has shown an increased R0 resection rate in pts with BR/LA PDAC, providing the rationale to explore the combination of other TGF-β targeting agents with FOLFIRINOX in the neoadjuvant setting (PMID: 34884782; PMID: 31145418). NIS793 is a first-in-class monoclonal antibody that directly binds TGF-β and reduces intratumoral fibrosis in preclinical models (PMID: 33298926). NIS793 also has an acceptable safety profile and preliminary clinical activity. This study investigates whether NIS793 modulation of the tumor fibrotic network improves clinical outcomes of FOLFIRINOX neoadjuvant therapy in BR/LA PDAC. Our aim is to demonstrate how TGF-β inhibition and stroma remodeling contribute to clinical outcomes. Methods: This is a single institution, open label, 2-part, 2-arm, non-comparator, Phase Ib study (NCT05417386) of FOLFIRINOX + NIS793 as neoadjuvant therapy for pts with untreated BR/LA PDAC. Eligible pts are adults with measurable disease, adequate organ and bone marrow function, and ECOG PS ≤1. In Part 1 (safety run-in), 6-18 pts with histologically confirmed untreated metastatic PDAC receive FOLFIRINOX + NIS793 at different dose levels. Dose escalation is primarily guided by the number of dose-limiting toxicities. Primary objectives are assessing safety, defining the recommended Phase II dose (RP2D), and providing initial evidence of clinical benefit of the combination. In Part 2, pts with untreated BR/LA PDAC are randomized 4:1 and stratified by BR vs LA. Pts in Arm 1 (n=5) receive 8 cycles of FOLFIRINOX followed by chemoradiation therapy (CRT) and surgery. Pts in Arm 2 (n=23) receive 8 cycles of FOLFIRINOX + NIS793 at RP2D followed by CRT + NIS793, surgery, and 12 cycles of adjuvant NIS793. The primary endpoint is R0 resection rate. Secondary endpoints are disease-free survival, progression-free survival, overall survival, and pathologic complete response. The effect of neoadjuvant therapy will be assessed by ferumoxytol-MRI, circulating cell-free DNA dynamics analysis, single-cell RNA sequencing, immunohistochemistry, and digital spatial analysis. Together, these correlative analyses may enable development of a mechanistic model for TGF-β inhibition in PDAC. This study is ongoing. The first pt was treated on Aug 2, 2022. Clinical trial information: NCT05417386 .