Abstract B002: Effects of Proglumide with Chemotherapy on the Pancreatic Tumor Microenvironment: Phase 1 PROGEM Trial

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis and resistance to therapy that is attributed to its desmoplastic and immunosuppressive tumor microenvironment (TME). In animal models of PDAC, the cholecystokinin-B receptor (CCK-BR) antagonist, proglumide, was shown to decrease tumoral fibrosis, alter the tumor immune cell signature, and allow increased uptake of chemotherapy and T-cells into tumors resulting in decreased metastases and improved survival. The purpose of this Phase 1 clinical trial was to study the safety of proglumide in combination with standard of care chemotherapy with gemcitabine/nab-paclitaxel (GEM-NAB-P) in subjects with metastatic PDAC. The secondary aim was to study the combined effects of proglumide with GEM-NAB-P on the TME with tumor biopsies and a blood biomarker assay. Methods: The study was an open-labeled Phase 1 trial in gemcitabine-naïve subjects with metastatic PDAC with ECOG 0-1 performance status. The study was approved by the FDA, IRB and registered on the clinicaltrials. gov website (NCT05827055). Subjects were treated with standard of care GEM-NAB-P with oral proglumide 1200mg/day until progression. Safety was assessed with adverse events according to CTCAE criteria. Tumor biopsies were obtained at baseline and again at week-8 on therapy and analyzed by histology and multiplex immunohistochemistry for changes in the TME. A liquid biopsy serum sample was collected at baseline, week-8 and at the end-of treatment (EOT) for analysis of a microRNA biomarker panel reflecting changes in the TME. McGill pain surveys were done at baseline, week 8 and at the EOT. Results: Six patients were enrolled and treated in the study and no AEs related to proglumide were reported. Compared to baseline, week-8 biopsies showed an 81% decrease in Ki67+ cells; a 75% decrease in M2-polarized tumor-associated macrophages; a 42% decrease in tumor collagen content, and a 13-fold increase in CD8 T-cells. A blood biomarker panel done before and on treatment showed changes that correlated with the histology and the clinical course. The anti-fibrotic markers (miR185, miR346, and miR378) and the inhibitors of epithelial to mesenchymal transition (miR200 and miR205) increased with therapy. MiR122 that regulates cell cycle and growth decreased initially but increased at the time of progression. The McGill pain survey showed reduced pain level at week 24 or EOT. Conclusion: These results showed that proglumide is safe in combination with chemotherapy for subjects with metastatic PDAC. A parallel shift occurs between the TME and circulating microRNA profiles offering a promising non-invasive biomarker panel for monitoring treatment response. Because proglumide monotherapy (and not gemcitabine) remodeled the TME in murine models of PDAC, our data suggest that proglumide also may alter the TME in human subjects with PDAC and warrants further investigation in a Phase 2 clinical trial. Citation Format: Jill P. Smith, Gakiza Christal. Nkulikiyimana, Hong Cao, Wenqiang Chen, Bhaskar Kallakury, John Kwagyan, Benjamin A. Weinberg. Effects of Proglumide with Chemotherapy on the Pancreatic Tumor Microenvironment: Phase 1 PROGEM Trial abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85 (18Suppl₃): Abstract nr B002.