• Has histological confirmation of colorectal cancer

• Received post-R0 resection of stages II, III, or IV colorectal cancer and has completed all planned curative intent therapies that must include ≥ 3 months of oxaliplatin containing chemotherapy

• Has no definitive evidence of radiographic disease per assessment by investigators within 28 days (before or after) a positive ctDNA assay

• Has minimal residual disease as defined by positive ctDNA assay (completed as standard-of-care at MD Anderson). Patients may be identified for enrollment with any Clinical Laboratory Improvement Amendments (CLIA)-certified ctDNA assay for MRD. MRD status will be confirmed with the Signatera assay prior to initiation of therapy (unless the prior testing was also done with Signatera in which case this test would not require confirmation)

• Has adequate organ and marrow function as defined below:

‣ absolute neutrophil count: ≥1,000/mcL

⁃ platelets: ≥100,000/mcL

⁃ total bilirubin: ≤ institutional upper limit of normal (ULN)

⁃ AST(SGOT)/ALT(SGPT): ≤3 × institutional ULN

⁃ Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥60 mL/min. Creatinine clearance (Clcr) can either be measured in a 24-hour urine collection or estimated by the Cockcroft-Gault equation as follows: Clcr (mL/min) = \[(140 - age) x (weight in kg) ÷ \[72 x (serum creatinine in mg/dL)\] \[0.85 if female\]

• Has ECOG performance status (PS) of 0 or 1

• Is of age ≥ 18 years. Because no dosing or adverse-event data are currently available on the use of TAS-102 in patients, children \<18 years of age are excluded from this study.

• Is able to understand and is willing to sign a written informed consent document.

• Is willing to utilize contraception. Female subjects agree to use highly effective contraception combined with an additional barrier method (eg, diaphragm, with a spermicide) while on study and for 7 months after last dose of study drug, and the same criteria are applicable to male subjects if they have a partner of childbirth potential. Male subject agrees to use a condom and not donate sperm while in this study and for 7 months after the last treatment.