Abstract CT030: Randomized placebo-controlled, biomarker-stratified phase 1b microbiome modulation trial for metastatic melanoma demonstrates impact of antibiotic pre-conditioning regimen on the microbiome and immunity

Abstract Background: Gut microbiota modulation shows promise in improving immune checkpoint blockade (ICB) response; however, precision biomarker-driven trials using rationally-designed consortia are lacking. To address this, we performed a multi-center, randomized placebo-controlled, biomarker-stratified phase 1 trial in patients with ICB-naïve unresectable or metastatic melanoma using SER-401, a bacterial consortia enriched for Firmicutes spores and Ruminococcaceae. Methods: MCGRAW was a multi-center, randomized, blinded, and placebo-controlled phase 1b study in patients with advanced melanoma. Patients were randomized 2: 1 to the SER-401 active or placebo arm, respectively, and stratified by baseline stool Ruminococcaceae abundance. Patients received an oral vancomycin (vanco) preparative regimen+SER-401 (vanco+SER-401 arm), versus placebo antibiotic+placebo (Placebo arm), followed by nivolumab. Stool, blood and tumor samples were collected at baseline and on treatment. The primary endpoint was safety, with additional secondary endpoints (SER-401 microbiome engraftment, overall response rate (ORR), disease control rate (DCR), and other translational endpoints). The study was not powered for comparison between arms. Results: 14 patients were randomized (n=8 vanco+SER-401, n=6 placebo). In the vanco+SER-401 arm, ORR was 25. 0% and DCR was 37. 5%, with no Grade 3-4 treatment-related adverse events (TRAE) ; in the placebo arm, ORR was 66. 7% and DCR was 83. 3%, with 1 (17%) TRAE. Notably, pre-conditioning with vanco was associated with significant shift in the microbiome taxonomic composition, with depletion of target families such as Ruminococcaceae (p=0. 008, Wilcoxon signed-rank test), and other spore-formers, followed by their recovery post dosing with SER-401. There was a significant increase in multiple ICB-resistance associated pathways (e. g. butyrate synthesis, p0. 0001), and a decrease in response-associated pathways after vanco preconditioning; these changes did normalize by nivolumab initiation. There was corresponding increase in systemic proteomic markers of inflammation after vanco, which also normalized by first dose of immunotherapy. Conclusions: This first-of-its-kind, placebo-controlled, randomized biomarker-driven microbiome modulation trial demonstrated that SER-401 and anti-PD1 are a safe combination in melanoma patients. The study was limited by poor accrual during the COVID-19 pandemic. Nonetheless, important insights were gained via translational analyses, suggesting that antibiotic preconditioning and interventional drug dosing regimens should be carefully considered when designing such trials. Additional placebo-controlled biomarker-driven microbiome trials are needed in this age of precision medicine. Trial registration: ClinicalTrials. gov (NCT03817125) Citation Format: Isabella C. Glitza Oliva, Yongwoo David Seo, Christine N. Spencer, Jennifer R. Wortman, Elizabeth M. Burton, Farah A. Alayli, Christopher Loo, Shikha Gautam, Ashish V. Damania, Julie Densmore, Justin Fairchild, Christopher Cabanski, Matthew C. Wong, Christine B. Peterson, Brian Weiner, Nathan Hicks, John Aunins, Christopher McChalicher, Michael T. Tetzlaff, Omid Hamid, Patrick A. Ott, Genevieve M. Boland, Ryan J. Sullivan, Kenneth F. Grossmann, Nadim J. Ajami, Theresa M. LaVallee, Matthew R. Henn, Hussein A. Tawbi, Jennifer A. Wargo. Randomized placebo-controlled, biomarker-stratified phase 1b microbiome modulation trial for metastatic melanoma demonstrates impact of antibiotic pre-conditioning regimen on the microbiome and immunity abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (7Suppl): Abstract nr CT030.