Phase I GlutaPanc Trial: l-Glutamine Plus Gemcitabine/Nab-Paclitaxel Shows Promising Efficacy in Advanced Pancreatic Cancer
核心洞察
A single-arm phase I trial combining oral l-glutamine with gemcitabine and nab-paclitaxel (GA) in 16 advanced pancreatic ductal adenocarcinoma (搜索) (PDAC) patients achieved a 44% objective response rate, including two complete responses.
The recommended phase 2 dose was established at 30 g/day oral l-glutamine with full standard doses of gemcitabine (1,000 mg/m²) and nab-paclitaxel (125 mg/m²), with manageable toxicity and no treatment-related discontinuations.
Median overall survival reached 22 months with a 12-month OS rate of 69%, substantially exceeding the historical median OS of 258 days for first-line GA alone in metastatic PDAC.
A single-arm, dose-finding phase I trial has demonstrated encouraging efficacy signals for oral l-glutamine added to first-line gemcitabine and nab-paclitaxel (GA) chemotherapy in patients with advanced pancreatic ductal adenocarcinoma (搜索) (PDAC). The GlutaPanc study, conducted at Cedars-Sinai Medical Center and published in Nature, enrolled 16 evaluable subjects (15 metastatic and one locally advanced or unresectable) between May 13, 2021 and June 2, 2023, with the most common metastatic sites being the liver, lung, peritoneum and lymph nodes.
The combination produced a best overall response rate (ORR) of 44%, comprising two complete responses (CRs) and five partial responses (PRs), corresponding to a CR rate of 12.5%. Tumor reduction was observed in 94% of subjects (15 of 16), with a mean reduction in tumor target lesions from baseline of −34.1% ± 37.7%. Eight subjects experienced stable disease and one subject had progressive disease as the best response.
Survival Outcomes
The median overall survival (OS) was 22 months (95% CI 11–not reached), with 12-month and 24-month OS rates of 69% (95% CI 49–96%) and 40% (95% CI 19–84%), respectively. The median progression-free survival (PFS) was 8.5 months (95% CI 6–not reached), with 6-month and 12-month PFS rates of 69% (95% CI 49–96%) and 25% (95% CI 11–58%), respectively. These outcomes compare favorably against the historical median OS of 258 days and median PFS of 167 days for first-line GA alone in metastatic PDAC, which served as the benchmark for defining "long" versus "short" survival in correlative analyses.
Dose Finding and Safety
The trial employed a Bayesian adaptive design incorporating the extended escalation with overdose control (EWOC) algorithm to determine the recommended phase 2 dose (RP2D). All 16 subjects completed a 1-week oral l-glutamine lead-in before receiving a median of eight cycles (range 2–15) of GA and l-glutamine. The RP2D was estimated as dose level 2, corresponding to maximum doses of oral l-glutamine (30 g per day) with full standard doses of gemcitabine (1,000 mg/m²) and nab-paclitaxel (125 mg/m²).
l-Glutamine was generally well tolerated, with most treatment-related adverse events consistent with the chemotherapy backbone. Three dose-limiting toxicities (DLTs) were encountered during the assessment window, all deemed treatment-related to GA rather than oral l-glutamine. Notably, there were no treatment-related study discontinuations. Of the 14 subjects who discontinued the study, 12 did so because of disease progression and two because of cancer-related death.
Metabolic and Microbiome Correlates
Preplanned correlative analyses revealed on-target effects of l-glutamine supplementation. Plasma glutamine concentrations were significantly elevated with l-glutamine treatment compared to baseline, with downstream increases in l-alanine and l-proline levels, consistent with glutamine serving as a precursor for both amino acids. Anaplerosis and nucleotide biosynthesis were elevated in the pentose phosphate pathway and UDP-GlcNAc pathway, while fatty acid and cholesterol metabolites were depleted.
The study also assessed intestinal microbiome composition via shotgun metagenomics. l-Glutamine did not significantly alter alpha diversity (Shannon index, P = 0.24) or beta diversity (Bray–Curtis dissimilarity, R² = 0.025, P = 0.99). However, participants experiencing longer survival on glutamine-based therapy had reduced abundance of gram-negative bacteria at baseline and after treatment. A significant association was observed in participants with short PFS, who exhibited higher basal alpha diversity compared to those with long PFS (P = 0.01).
Importantly, l-glutamine treatment improved gut barrier function, as evidenced by a significant reduction in circulating lipopolysaccharide (搜索) (LPS) levels, even in the presence of GA for all subjects. Responders had reduced downstream pathogen-associated molecular pattern activation, with proinflammatory CCL11 (搜索) and IL-33 (搜索) significantly lower in responders compared to nonresponders.
Study Design and Limitations
This was a single-institution, open-label, single-arm, nonrandomized phase I trial enrolling participants with untreated advanced PDAC (locally advanced, unresectable or metastatic disease) who were planned to receive standard GA chemotherapy. Participants aged ≥18 years with histologically confirmed advanced PDAC were eligible, provided systemic therapy had not been received in the first-line metastatic setting. Exclusionary criteria included parenteral nutrition, enteral feeding, or use of any other nutritional supplement.
The study authors note that cancer phase I trials are designed to estimate the MTD or RP2D rather than to test a specific hypothesis, and are not powered to favor a particular alternative hypothesis. The dose-finding nature of the trial, with single participants enrolled into various dosing combinations, precludes replication. The authors state that "advancement of these positive findings into subsequent phase 2 or 3 trials would be warranted to confirm the safety and efficacy signals seen in this trial." The exploratory, outcome-informed nature of selecting and stratifying nucleotide biosynthesis metabolites also warrants further evaluation in a larger study for validation as potential biomarkers.
The study was approved by the Institutional Review Board of Cedars-Sinai Medical Center and registered on ClinicalTrials.gov (NCT04634539) as of November 18, 2020.