Background: Currently, there are no biomarkers validated prospectively in randomized studies for resected colon cancer (CC) to determine need for adjuvant chemotherapy (AC). However, circulating tumor DNA (ctDNA) shed into the bloodstream represents a highly specific and sensitive approach (especially with serial monitoring) for identifying microscopic or residual tumor cells in CC patients (pts) and may outperform traditional clinical and pathological features in prognosticating risk for recurrence. CC pts who do not have detectable ctDNA (ctDNA-) are at a much lower risk of recurrence and may not need AC. Furthermore, for CC pts with detectable ctDNA (ctDNA+) who are at a very high risk of recurrence, the optimal AC regimen has not been established. We hypothesize that for pts whose colon cancer has been resected, ctDNA status may be used to risk stratify for making decisions about AC. Methods: In this prospective phase II/III trial, up to 1,912 pts with resected stage III A, B (all pts) and stage II, IIIC (ctDNA+ only) CC will be enrolled. Based on the post-operative ctDNA status using Natera’s Signatera assay, those who are ctDNA- (Cohort A) will be randomized to immediate AC with fluoropyrimidine (FP) + oxaliplatin (Ox) for 3-6 mos per established guidelines vs serial ctDNA monitoring. Patients who are ctDNA+ post-operatively or with serial monitoring (Cohort B) will be randomized to FP + Ox vs more intensive AC with addition of irinotecan (I) for 6 mos. The primary objectives for Cohort A are time to ctDNA+ status (phase II) and disease-free survival (DFS) in phase III in the immediate vs delayed AC arms. The primary objective for Cohort B is DFS in the FP + Ox vs FP + Ox + I arms for both phase II and phase III portions of the trial. Secondary objectives include prevalence of detectable ctDNA post-operatively, time-to event outcomes (overall survival & time to recurrence) by ctDNA status, and the assessment of compliance to adjuvant therapy. Biospecimens including archival tumor tissue, post-operative and serial matched/ normal blood samples will be collected for exploratory correlative research. Study will activate in early 2022 across the NCTN. NCT#: Pending. Support: U10-CA-180868, -180822; UG1CA-189867; Natera.