A phase 0, window of opportunity study of parasympathetic stimulation with bethanechol in localized pancreatic adenocarcinoma prior to surgery.

Background: The parasympathetic branch of the autonomic nervous system has shown tumor-suppressive effects in preclinical models of pancreatic adenocarcinoma (PDAC) by inhibiting cancer stem cells and suppressing inflammatory cytokine production. Based on these findings, we hypothesized that bethanechol, an FDA-approved parasympathomimetic agent targeting muscarinic receptors, could enhance treatment efficacy in PDAC.

Methods: We conducted a phase 0/window of opportunity study evaluating short-term parasympathetic activation with fixed dose bethanechol (100 mg twice daily) in subjects with resectable or borderline resectable PDAC prior to surgery. The primary endpoint was a change in cell proliferation by Ki-67 expression compared to stage-matched controls. Secondary endpoints included tissue expression of stem cell markers (CD44), infiltrating immune cells (CD8a, Granzyme B, and CD68), and changes in circulating inflammatory cytokine concentrations.

Results: Seventeen patients were enrolled with 13 eligible for analysis of endpoints. Median age was 74 (59-86), 6 female (46%), all ECOG 0-1, and median duration of treatment was 8 days (7-13). R0 resections were achieved in 9 patients (69%). There was no difference in Ki67 and CD44 tissue biomarkers between bethanechol-treated and control samples. Decreased numbers of Granzyme B-expressing cells were seen in bethanechol-treated tissues. Bethanechol treatment was associated with the suppression of circulating IL-18. The most common treatment-related adverse events (TRAE) were hot flashes (30.7%), urinary frequency (15.4%), increased salivation (15.4%), hyperhidrosis (7.7%), and nausea (7.7%). There were no Grade 3 or higher adverse effects. No surgical complications were attributed to bethanechol treatment.

Conclusion: Bethanechol 100 mg twice daily is well tolerated in patients with PDAC in this small phase 0/window of opportunity study (NCT03572283). Bethanechol treatment was associated with decreased Granzyme B positive cells and decreased circulating IL-18 consistent with an anti-inflammatory role for parasympathetic muscarinic signaling in PDAC.