l-Glutamine in combination with first-line gemcitabine and nab-paclitaxel in advanced pancreatic ductal adenocarcinoma: an open-label, single-arm, phase 1 GlutaPanc trial

Exogenous l -glutamine has preclinical antitumor activity although formal clinical translation has not been attempted. We conducted a single-arm phase 1 trial to assess the safety and preliminary efficacy of clinical-grade, US Food and Drug Administration-approved l -glutamine therapy with gemcitabine and nab-paclitaxel (GA) in participants with treatment-naive, advanced pancreatic cancer ( n = 16). The primary endpoint was to determine the recommended phase 2 dose (RP2D) by adaptive Bayesian design across standard doses of GA and a dose range of 0.1–0.3 g kg −1 twice-daily oral l -glutamine. Secondary endpoints included safety and preliminary efficacy of the study combination. The primary endpoint was met with the RP2D reached at maximum doses of l -glutamine and GA. The grade ≥3 treatment-related adverse event rate was 66.7%, primarily from GA. Addition of l -glutamine to GA induced tumor shrinkage in 94% of subjects with a best overall response rate (ORR) of 44% (12.5% complete response). Median progression-free survival and overall survival (OS) were 8.5 months (95% confidence interval (CI) 6–not reached (NR)) and 22 months (95% CI 11–NR), respectively. l -Glutamine induced distinct metagenomic and metabolomic signatures on exploratory analyses in glutamine-treated subjects as a single agent, while the combination of l -glutamine and GA nearly doubled the ORR and tripled the OS compared to historical GA alone (ClinicalTrials.gov registration: NCT04634539 ).