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

Background: The primary aim of this Phase 1 clinical trial was to study the safety and dose of a cholecystokinin receptor antagonist, proglumide, in combination with gemcitabine/nab-paclitaxel (GEM-NAB-P) in patients with metastatic pancreatic cancer. The secondary aim was to study the effects of proglumide with GEM-NAB-P on the tumor microenvironment (TME) with tumor biopsies and a blood biomarker assay. An exploratory aim studied the effects of proglumide treatment on cancer-related pain. Methods: Gemcitabine-naïve patients were treated with GEM-NAB-P plus proglumide 1200 mg/day. Tumor biopsies and a liquid biopsy serum sample for analysis of a microRNA biomarker panel were collected pre- and on-treatment to study the TME. McGill pain surveys were done at baseline, week 8 and at the end of treatment. The study was approved and registered (NCT05827055). Results: The mean age of the patients was 68.2 years (range 54-74 years). The starting dose was well-tolerated with no unexpected treatment-related adverse events observed. Multiplex immunohistochemical analysis of tumor biopsies at baseline and week 8 revealed a significant reduction in Ki67+ cells, collagen1α1, and M2-polarized tumor-associated macrophages (TAMs). Week 8 tumor biopsies demonstrated a significant increase in CD8+ T-cells and natural killer cells compared to baseline. The blood biomarker panel showed a significant inverse change in microRNAs associated with decreasing fibrosis and metastasis. The McGill pain scores showed less pain at week 24 or end-of-treatment compared to baseline. Conclusions: Proglumide demonstrates a favorable safety profile when combined with standard chemotherapy for metastatic pancreatic cancer. Its unique ability to remodel TME and alleviate cancer-related pain highlights its potential, warranting further research.