My long term goal as a clinical scientist at MD Anderson Cancer Center is to lead clinical trials that improve survival for patients with gastrointestinal malignancies, particularly colorectal and anal cancer. To accomplish this, I have integrated novel testing techniques and promising immunotherapy combinations into the design of NCI-supported clinical trials. I am the overall Principal Investigator for the NRG-GI005 phase II/III trial evaluating circulating tumor DNA (ctDNA) as a predictive biomarker for adjuvant chemotherapy benefit in patients with stage IIA colon cancer. NRG-GI005 is the first NCI-supported trial for any solid tumor type to incorporate ctDNA as an integral biomarker for treatment assignment as part of a clinical trial design. Planned analysis of optional blood collected on this study will compare head-to-head different methodologies for detecting minimal residual disease (MRD) performed on the same samples and provide missing insights into optimal ctDNA assay selection needed for future NCI trials evaluating ctDNA as a surrogate for the presence of MRD. I have also written and led, as overall PI, two immunotherapy trials across NCTN (SWOG S2107) and ETCTN (NCI 9673) sites. Promising clinical activity for the triple therapy of encorafenib, cetuximab, and nivolumab for patients with microsatellite stable BRAFV600E metastatic colorectal cancer from a pilot trial at MD Anderson were applied for the subsequent SWOG S2107 randomized phase II trial, now activated across the NCTN. The ETCTN-sponsored NCI 9673 trial demonstrated antitumor activity of nivolumab metastatic anal cancer and led to this treatment as a recommended option on the NCCN Guidelines for anal cancer. As an R50 funded clinical scientist, I propose to combine these clinical trial leadership experiences and expand on the role of blood-based biomarkers to generate novel combination immunotherapy trials. I have utilized extravesicle RNA (evRNA) isolated from plasma to characterize changes in RNA signatures associated with treatment response to encorafenib, cetuximab, and nivolumab in patients with BRAFV600E metastatic colorectal cancer. With R50 protected effort, I will expand plasma evRNA analysis in evaluating response using samples collected from SWOG S2107, with >90% yield from patients enrolled thus far. During the funding period, I also propose to develop my leadership institutionally in my role as SWOG PI for the NCTN LAPS grant Executive Committee, where I will expand enrollment at new affiliate sites for MD Anderson, prioritizing SWOG/NCTN trials first, which we also anticipate will improve underrepresented minority enrollment and address health disparities on NCI trials conducted under MD Anderson umbrage. If successful, these efforts collectively could serve as justification to expand the utility of liquid biopsy beyond ctDNA, with the goal of applying translational studies to identify effective therapeutic strategies for all patients with gastrointestinal ...