A study evaluating microbiome modulation therapy in patients undergoing first-line therapy for metastatic colorectal cancer.

TPS3679 Background: Colorectal cancer (CRC) is the second leading cause of cancer-related mortality worldwide. Despite advances in systemic therapy, the 5-year overall survival for metastatic CRC remains poor. Emerging evidence suggests that the gut microbiome influences CRC development, progression, as well as chemotherapy resistance. There is strong preclinical data showing the association of Fusobacterium nucleatum and Escherichia coli with poor outcomes and chemotherapy resistance in patients with CRC. Younger patients and Black patients have been found to have a high-level colonization with F nucleatum , which could potentially contribute to healthcare disparities. If the amount of cancer-associated bacteria in the microbiome can be reduced, patients may respond better to chemotherapy and have improved outcomes. Preclinical studies indicate that targeting these bacteria with antibiotics may enhance chemotherapy efficacy. Aspirin may also be beneficial as it affects gene expression and inhibits Fusobacterium nucleatum with differential effects at varying drug concentrations. Our study evaluates the feasibility, safety, and preliminary efficacy of adding Microbiome Modulation Therapy (MBMT), including ciprofloxacin, metronidazole, +/- aspirin, to standard first-line chemotherapy in patients with metastatic CRC. Methods: This is a two-arm, noncomparative phase II trial enrolling adults (≥18 years) with stage IV CRC and measurable disease by RECIST 1.1. Eligible patients must have ECOG performance status 0–2 and planned first-line 5FU-based standard of care chemotherapy. Patients are excluded if they have recent antibiotic use to treat an infection within 30 days of treatment start (prophylactic preoperative antibiotics are allowed), have had a total colectomy, or are taking probiotic treatments. Patients are randomized to standard chemotherapy alone (investigators choice) or chemotherapy plus MBMT (ciprofloxacin, metronidazole, +/- aspirin for 28 days). The primary endpoint is objective response rate (ORR) per RECIST 1.1. Secondary endpoints include overall survival (OS), progression-free survival (PFS), safety, and tolerability of MBMT. Exploratory endpoints include changes in microbiome composition as measured by shotgun sequencing of fecal samples at baseline and after one month of treatment with chemotherapy +/- MBMT. Correlative studies will use shotgun sequencing to assess microbiome signatures, microbiota diversity, and changes with treatment. Correlative analyses will explore microbiome modulation as a novel therapeutic strategy to overcome chemoresistance in metastatic CRC. Enrollment is ongoing at Virginia Commonwealth University Massey Comprehensive Cancer Center in Richmond, Virginia. Clinical trial information: NCT06728072 .