Background: GP-2250 is a metabolic enzyme inhibitor that selectively induces oxidative stress, mitochondrial dysfunction, and apoptosis in cancer cells by inhibiting glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and limiting aerobic glycolysis, an essential process for energy production in cancer cells. In vitro, increasing concentrations of GP-2250 induced proportional dose-response effects in 5 different pancreatic cancer cell lines (Buchholtz BMC Cancer 2017). Patient-derived pancreatic xenograft studies in mice demonstrated tumor growth inhibition with GP-2250 monotherapy (Braumann J Clin Oncol 2020). In combination with gemcitabine, a synergistic effect was shown with greater inhibition of pancreatic tumor growth than with either gemcitabine or GP-2250 alone. These findings support the assessment of the therapeutic potential of GP-2250 in combination with gemcitabine in patients with pancreatic cancer. Methods: This open-label phase 1/2 trial will evaluate the safety and tolerability of escalating doses of GP-2250 and the preliminary efficacy of GP-2250 in combination with gemcitabine in patients with advanced unresectable or metastatic pancreatic adenocarcinoma who have progressed on prior treatment with FOLFIRINOX chemotherapy. In phase 1, Bayesian Optimal Interval design will be used for GP-2250 dose escalation. The dose-limiting toxicity (DLT)–assessment period will be 5 weeks at each dose level (starting dose 250 mg once weekly intravenously), consisting of a 1-week run-in period with GP-2250 monotherapy, followed by a full cycle of GP-2250 plus standard dose and schedule of gemcitabine. Single patient cohorts (100% dose escalation between cohorts) will be enrolled until the occurrence of the first DLT (or cohort 4 if no DLTs occur in cohorts 1−3), after which, cohorts will be expanded to 3 patients with 35%−45% dose escalations between cohorts. Patients will receive treatment until disease progression or development of unacceptable toxicity. Primary study endpoints include safety and tolerability of GP-2250, tumor response (RECIST 1.1), disease control rate (complete response, partial response, stable disease), and duration of response. Pharmacokinetics, incidence and severity of laboratory abnormalities and treatment-emergent adverse events, progression-free survival, and overall survival will also be assessed. As of September 2021, 19 patients have been enrolled. Following completion of the phase 1/2 trial, a phase 3 first-line maintenance study will be initiated. This study is funded by Geistlich Pharma AG. Clinical trial information: NCT03854110. Clinical trial information: NCT03854110.