593 First-in-human evaluation of the safety, tolerability, and gut microbial composition of a live biotherapeutic product GB104 in patients with colorectal cancer

<h3>Background</h3> GB104 is an orally administered investigational live biotherapeutic product composed of a lyophilized single bacterial strain of <i>Lactiplantibacillus plantarum.</i> In preclinical research, we found that monotherapy of GB104 can inhibit tumor growth in various syngeneic murine cancer models with potent immunomodulatory activity and various anti-tumorigenic mechanisms. In this study, we conducted a study to evaluate the safety, tolerability, and explore changes in gut microbiota composition after monotherapy of GB104 in patients with colorectal cancer who completed curative colectomy and planned therapy of colorectal cancer. <h3>Methods</h3> We did an open-label, prospective, dose-escalation, phase 1 study at a single-center in Seoul, Korea. This dose-escalation cohort study was designed using a standard 3 + 3 protocol. Patients in each cohort administered GB104 orally once daily in 28-day cycles until unacceptable toxicity, disease progression, or patient withdrawal. The initial dose level was one capsule containing 2 X 10¹⁰ ~ 2 X 10¹¹ of GB104 per capsule, and the subsequent dose levels were three and five capsules. Progression to the next dose level was determined by the Safety Review Committee (SRC) based on their evaluation of safety data. The primary outcome was to evaluate the safety and tolerability by assessing dose-limiting toxicity (DLT) and to determine the maximum tolerable dose (MTD). Exploratory outcomes included taxonomic analysis of gut microbial composition, the European quality of life 5 Dimensions 5 Levels (EQ-5D-5L) for quality of life, and the low anterior resection syndrome (LARS) score for bowel function, and an assessment of GB104 compliance. <h3>Results</h3> A total of nine patients were enrolled during the trial. GB104 was found to be safe and well-tolerated across all doses, with no DLTs observed. Compliance (99.6%) with the medication regimen was high across all cohorts. Stable EQ-5D-5L scores indicated consistent quality of life, while LARS scores showed dose-dependent improvement in bowel function, suggesting a favorable safety profile and potential benefits for GB104. Taxonomic analysis revealed minimal changes in microbial diversity across cohorts, indicating that GB104 did not significantly alter the gut microbiome. <h3>Conclusions</h3> This study demonstrated the safety profile and tolerability of GB104 administered at doses of one, three, and five capsules QD orally in patients who had completed curative colectomy and planned therapy of colorectal cancer. The administration of up to five capsules once daily was found to be the maximum tolerated dose and is recommended for the phase 2 dose. <h3>Trial Registration</h3> NCT05943041. <h3>Ethics Approval</h3> GB104 was conducted in full accordance with Good Clinical Practice guidelines and the Declaration of Helsinki or the laws and regulations of the country in which the research was conducted, whichever afforded the most protection. Written informed consent was obtained from all the patients.