Background: The gut microbiome has emerged as a new therapeutic target to augment the efficacy of immune checkpoint blockade. MRx0518 is a novel, gut microbiome-derived, oral live biotherapeutic, designed to induce a broad immunostimulatory response to re-engage PD-1 inhibitor activity. Preclinical studies showed that MRx0518 reduced tumour growth in models of kidney, lung and breast cancer. MRx0518 increased CD4 and CD8 T cell and NK cell infiltration into the tumour and decreased Tregs. Upregulation of tumour TLR5 was observed and linked to the bacterial flagellin moiety, which was shown to strongly induce NFκB, cytokine responses and IFNγ+ CD4 and CD8 T cells. The study, one of the first oncology trials conducted with live biotherapeutics, is a single center, open label, safety and preliminary efficacy study of MRx0518 in combination with pembrolizumab in patients with solid tumors who have progressed on PD-1 inhibitors. Methods: Trial consists of 2 parts. In Part A, 12 patients receive pembrolizumab 200 mg every 3 weeks plus 1 capsule (bid) of MRx0518 with a DLT period of 1 cycle (21 days). In Part B, up to 30 patients per cohort (NSCLC, Urothelial, Renal and Melanoma) will receive pembrolizumab 200 mg every 3 weeks plus 1 capsule (bid) of MRx0518 for up to 35 cycles or until disease progression per RECIST 1.1. The primary end points are safety and tolerability of MRx0518 in combination with pembrolizumab (Parts A and B) and clinical benefit of MRx0518 in combination with pembrolizumab (Part B). Secondary end points are objective response rate, duration of response, disease control rate, and progression-free survival. Exploratory end points include biomarkers of treatment effect, effect on microbiota and overall survival. Recruitment is ongoing. Clinical trial information: NCT03637803