Combination L-Glutamine with Gemcitabine and Nab-Paclitaxel in Treatment-Naïve Advanced Pancreatic Cancer: The Phase I GlutaPanc Study Protocol

Abstract

Advanced pancreatic cancer is underscored by progressive therapeutic resistance and a dismal 5-year survival rate of 3%. Preclinical data demonstrated glutamine supplementation, not deprivation, elicited antitumor effects against pancreatic ductal adenocarcinoma (PDAC) alone and in combination with gemcitabine in a dose-dependent manner. The GlutaPanc phase I trial is a single-arm, open-label clinical trial investigating the safety of combination L-glutamine, gemcitabine, and nab-paclitaxel in subjects (n = 16) with untreated, locally advanced unresectable or metastatic pancreatic cancer. Following a 7-day lead-in phase with L-glutamine, the dose-finding phase via Bayesian design begins with treatment cycles lasting 28 days until disease progression, intolerance, or withdrawal. The primary objective is to establish the recommended phase II dose (RP2D) of combination L-glutamine, gemcitabine, and nab-paclitaxel. Secondary objectives include safety of the combination across all dose levels and preliminary evidence of antitumor activity. Exploratory objectives include evaluating changes in plasma metabolites across multiple time points and changes in the stool microbiome pre and post L-glutamine supplementation. If this phase I clinical trial demonstrates the feasibility of L-glutamine in combination with nab-paclitaxel and gemcitabine, we would advance the development of this combination as a first-line systemic option in subjects with metastatic pancreatic cancer, a high-risk subgroup desperately in need of additional therapies.

“Just add small molecules” cell‐free protein synthesis: CombiningDNAtemplate and cell extract preparation into a single fermentation

“…The effectiveness of the single pass TM‐TX‐TL extract as a reagent source for a recently developed glutamine biosensor 41 was tested. Because of its clinical relevance as a biomarker for cancer, severe infection, anorexia nervosa, kidney disease, and diabetes, glutamine monitoring is a desirable tool for patient‐specific optimization of treatment 37–45 . The glutamine biosensor is almost identical to a normal CFPS reaction, except that the reagents are modified to exclude the addition of glutamine as part of the PANOxSP SMM, and methionine sulfoximine (MSO) is added to inhibit the conversion of glutamate to glutamine by glutamine synthetase.…”

“…For a proof of concept, this system was tested in a glutamine biosensor with potential applications for monitoring cancer treatment and other diseases 37–45 . The new system gave generally comparable results to previous work, 41 but at a greatly reduced cost.…”

Supraphysiological glutamine as a means of depleting intracellular amino acids to enhance pancreatic cancer chemosensitivity

“…It was su cient to inhibit growth of established tumors by the revealed mechanism of amino acid depletion. A current phase 1 clinical trial (NCT04634539) is evaluating whether L-Gln (Endari ® ) supplementation for PDAC patients receiving gemcitabine and Nabpaclitaxel is safe with preliminary evidence of anti-tumor activity as a secondary outcome measure [44]. Although repurposing of FDA approved L-Gln may allow for expeditious translation, the development of a clinically viable D-Gln formulation would best re ect the bene ts of the gemcitabine-induced synthetic lethality observed in the preclinical studies here.…”

Glutamine Supplementation as an Anticancer Strategy: A Potential Therapeutic Alternative to the Convention

“…However, high doses of glutamine supplementation in certain contexts, particularly in patients with gastrointestinal cancers, have raised questions about the theoretical risk of fueling cancer growth. We are currently investigating the safety and feasibility of a combination of gemcitabine and nab-paclitaxel with oral L-glutamine powder as a first-line systemic therapy in patients with unresectable or metastatic PDAC (GlutaPanc phase I trial [ 124 ]). This will be the first-ever prospective trial to employ a dose-finding design of an approved oral L-glutamine therapy along with first-line standard chemotherapy in untreated metastatic PDAC.…”