Background: Circulating tumor DNA (ctDNA) has emerged as a novel marker with high specificity and positive predictive value for identifying radiographically occult microscopic or minimal residual disease (MRD) in colorectal cancer (CRC) patients (pts). An additional widely acknowledged unmet need is the development of therapeutic strategies to eradicate MRD and increase the cure rate of the disease. Ongoing trials are evaluating MRD as a biomarker for determining the intensity of post-operative adjuvant therapy. However, the feasibility and efficacy of therapy in pts who are MRD+ during surveillance (after all curative intent treatments including adjuvant chemotherapy) is unknown. Methods: In this proof-of-concept phase II study, pts with stages II-IV CRC noted to be MRD+ during surveillance (ctDNA+ but no radiographic evidence of disease on imaging in last 30 days) received 6 months (m) of TAS-102. Pts were identified through the MD Anderson INTERCEPT program that integrates MRD testing with a tissue informed assay (Signatera) into standard of care for CRC pts. The primary endpoint was 6-m ctDNA clearance and secondary objectives included 3-m ctDNA clearance, and disease-free survival (DFS). Assuming H0 = 5% spontaneous, HA = 30% ctDNA clearance with TAS 102 & 1-sided α = 0.05, 15 patients are required for β = 85%. Results: Between 7/22/22 and 9/7/23,15 pts with MRD were enrolled. Baseline characteristics included a median age of 62 years (range: 37-73), Caucasian (77%), male (77%), resected Stage IV (92%) and median ctDNA level of 1.55 MTM/ml (range 0.04-28.72). At data cutoff, 11 pts had 3-m ctDNA levels and 10 had a decrease in their ctDNA level (91%) including 5 with undetectable levels (45%). At 6-m, 60% of patients had ctDNA levels at or below prior levels; three maintained undetectable ctDNA at 6-m: of those, two pts had subsequent radiographic progression following therapy completion. Median DFS was 9.4-m in the full cohort. Conclusions: We demonstrate the feasibility of identifying and enrolling MRD+ pts through screening during surveillance onto therapeutic trials and show the ability of an experimental therapy to convert patients to MRD negative status, a necessary but not sufficient step for disease eradication. Preliminary results suggest that treatment with TAS-102 is effective in inducing ctDNA clearance in the short term in most pts, but with no evidence of persistent clearance. Updated results including 6-m ctDNA levels and survival data will be presented. Clinical trial information: NCT05343013.