4202 Background: PDAC has a poor prognosis and resistance to therapy due 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 increase chemotherapy uptake and T-cell infiltration into tumors, resulting in decreased metastases and improved survival. We sought to evaluate the safety of proglumide with GEM/NAB-P chemotherapy in pts with metastatic PDAC (mPDAC). Using tumor biopsies and a blood biomarker assay, we also studied the combined effects of proglumide with GEM/NAB-P on the TME. Methods: The PROGEM study was a phase 1 trial of proglumide 1200 mg PO daily, GEM 1000 mg/m2 IV, and NAB-P 125 mg/m2 IV days 1, 8, and 15 every 28 days in GEM-naïve pts with mPDAC (NCT05827055). The primary endpoints were safety and determination of the recommended phase 2 dose (RP2D). Safety was assessed with adverse events (AEs) according to CTCAE v. 5 criteria. Tumor biopsies were obtained pre-treatment and at 8 weeks on-treatment and analyzed by histology and multiplex immunohistochemistry for changes in the TME. A liquid biopsy serum sample was collected at baseline, week 8, and 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 EOT. Results: Six pts were enrolled. Three pts were treatment-naïve, and 3 had had prior mFOLFIRINOX. No AEs related to proglumide were reported. Five pts had stable disease, and 1 pt had disease progression as the best response, for a disease control rate of 83%. Median progression-free survival was 4 months, and median overall survival was 8.5 months. Compared to baseline, on-treatment 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. Pre- and on-treatment blood biomarkers showed changes correlated with histology and clinical course. Anti-fibrosis markers (miR185, miR346, and miR378) and inhibitors of epithelial to mesenchymal transition (miR200 and miR205) increased with therapy. MiR122, which regulates cell cycle and growth, decreased initially but increased at the time of progression. Pain scores showed improved pain at week 24 or EOT. Conclusions: Proglumide is safe in pts with mPDAC, and the RP2D is 1200 mg PO daily with standard dose GEM/NAB-P. Proglumide remodels the TME by decreasing fibrosis and immunosuppression while increasing T-cell infiltration. Changes in circulating microRNAs offer a promising non-invasive biomarker panel for monitoring treatment response. These results support further investigation of proglumide with GEM/NAB-P in a phase 2 clinical trial and future immunotherapy combinations. Clinical trial information: NCT05827055 .
Smith et al. (Wed,) studied this question.