Background: Differences in microbiome diversity and composition in immune checkpoint inhibitor (ICI)-responders vs non-responders have been demonstrated. Transplantation of responder feces in mouse models recapitulated the ICI-responsive phenotype. MET-4 is an oral alternative to fecal transplant consisting a well-defined mixture of intestinal bacteria isolated from healthy donor stool sample. We hypothesize that co-administration of MET-4 with ICI is safe and results in alterations of the gut microbiota. Methods: Three cohorts (n = 65) of subjects with any advanced solid tumor type treated with monotherapy anti- PD1/PD-L1 antibody outside of a therapeutic clinical trial will be enrolled. Group A: safety cohort of 5 subjects already on ICI will receive MET-4 in addition to standard of care (SOC) ICI. If < 2 subjects report adverse events of CTCAE grade ≥3 within 4 weeks at least possibly related to MET-4, this dose will be declared safe and groups B/C may start enrolling. Group B (n = 40): subjects with advanced solid tumors starting on ICI, randomized 3:1 to MET-4 plus SOC vs. SOC. Group C (n = 20): subjects with advanced solid tumors already on ICI with first unconfirmed disease progression randomized 1:1 to MET-4 plus ICI continuation vs. continuing ICI. Serial stool samples will be collected for taxonomic composition, diversity, metagenomics content and MET-4 species abundance. We anticipate the following analyses: 16S rRNA sequencing, shotgun metagenomics sequencing, qPCR, Nanostring nucleic acid detection and metabolomics profiling. Serial blood sampling for flow cytometry/CyTOF. Immune microenvironment of tumor specimen will be examined using immunohistochemistry. Other major inclusion criteria: willingness to provide correlative samples, RECIST v1.1 measurable disease and ECOG 0-2. Subjects unable to swallow oral medications are excluded. For the primary objective of cumulative relative abundance and changes of ICI-responsiveness associated species between baseline and day 12 MET-4, assuming a change of 0.5 standard deviation (SD) of microbial alpha diversity, our study will have ≥84% power to identify a significant difference given a significance level at 0.05 in group B. Assuming a change of 0.9 SD of microbial alpha diversity, we will have ≥83% power to identify a significant difference in group C. Response rates and progression free survival will be assessed per RECIST v1.1 and compared with historical data. Clinical trial information: NCT03686202