PRIMARY OBJECTIVES:
I. To compare the rate of ctDNA clearance in "ctDNA detected" patients treated with or without adjuvant chemotherapy following resection of stage IIA colon cancer. (Phase II) II. To compare recurrence-free survival (RFS) in "ctDNA detected" patients treated with or without adjuvant chemotherapy following resection of stage IIA colon cancer. (Phase III)
SECONDARY OBJECTIVES:
I. To describe the prevalence of detectable ctDNA in patients with stage IIA colon cancer following surgical resection.
II. To estimate time-to-event outcomes (overall survival \[OS\], recurrence-free survival \[RFS\], and time to recurrence \[TTR\]) by ctDNA marker status and treatment for patients with resected stage IIA colon cancer.
III. To estimate the rate of compliance with adjuvant chemotherapy and/or active surveillance for patients with resected stage IIA colon cancer.
Inclusion Criteria:
* The patient must have signed and dated an Institutional Review Board (IRB)-approved consent form that conforms to federal and institutional guidelines.
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
* Histologically/pathologically confirmed stage IIA adenocarcinoma of the colon (T3, N0, M0) with at least 12 lymph nodes examined at the time of surgical resection.
* Appropriate for active surveillance (i.e., no adjuvant chemotherapy) at the discretion of and as documented by the evaluating oncologist based on current practice patterns.
* The distal extent of the tumor must be \>= 12 cm from the anal verge on pre-surgical endoscopy (i.e., excluding rectal adenocarcinomas warranting treatment with chemoradiation). If the patient did not undergo a pre-surgical endoscopy, then the distal extent of the tumor must be \>= 12 cm from the anal verge as determined by surgical examination or pre-operative imaging.
* The patient must have had an en bloc complete gross resection of tumor (curative resection) as definitive surgical cancer treatment within 14 to 60 days of study randomization. Patients who have had a two-stage surgical procedure to first provide a decompressive colostomy and then, in a later procedure, to have the definitive surgical resection, are eligible.
* Availability and provision of adequate surgical tumor tissue for molecular diagnostics and confirmatory profiling.
* Absolute neutrophil count (ANC) must be \>= 1200/mm\^3 (within 28 days before randomization).
* Platelet count must be \>= 100,000/mm\^3 (within 28 days before randomization); and
* Hemoglobin must be \>= 9 g/dL (within 28 days before randomization).
* Total bilirubin must be =\< ULN (upper limit of normal) for the lab (within 28 days before randomization) unless the patient has a chronic grade 1 bilirubin elevation due to Gilbert?s disease or similar syndrome involving slow conjugation of bilirubin; and
* Alkaline phosphatase must be \< 2.5 x ULN for the lab (within 28 days before randomization); and
* Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) must be \< 1.5 x ULN for the lab (within 28 days before randomization).
* Serum creatinine =\< 1.5 x ULN for the lab or measured or calculated creatinine clearance \>= 50 mL/min using the Cockcroft-Gault formula for patients with creatinine levels \> 1.5 x ULN for the lab (within 28 days before randomization).
* Pregnancy test (urine or serum according to institutional standard) done within 14 days before randomization must be negative (for women of childbearing potential only).
* Patients receiving a coumarin-derivative anticoagulant must agree to weekly monitoring of international normalized ratio (INR) if they are randomized to Arm 2 and receive capecitabine.
Exclusion Criteria:
* Colon cancer histology other than adenocarcinoma (i.e., neuroendocrine carcinoma, sarcoma, lymphoma, squamous cell carcinoma, etc.).
* Pathologic, clinical, or radiologic evidence of overt metastatic disease. This includes isolated, distant, or non-contiguous intra-abdominal metastases, even if resected (including the presence of satellite nodules constituting N1c disease in the absence of lymph node involvement).
* Tumor-related bowel perforation.
* History of prior invasive colon malignancy, regardless of disease-free interval.
* History of organ transplantation.
* Any prior systemic chemotherapy, targeted therapy, or immunotherapy; or radiation therapy administered as treatment for colorectal cancer (e.g., primary rectal adenocarcinomas for which treatment with neoadjuvant chemoradiation is warranted are not permitted).
* Other invasive malignancy within 5 years before randomization. Exceptions are colonic polyps, non-melanoma skin cancer or carcinoma-in-situ including those of the cervix and breast (DCIS).
* Synchronous primary rectal and/or colon cancers.
* Antineoplastic therapy (e.g., chemotherapy, targeted therapy, or immunotherapy) within 5 years before randomization. (For the purposes of this study, hormonal therapy is not considered chemotherapy.).
* Uncontrolled cardiac disease, in the opinion of the treating medical oncologist, that would preclude the use of any of the drugs included in the GI005 treatment regimen. This includes but is not limited to:
* Clinically unstable cardiac disease, including unstable atrial fibrillation, symptomatic bradycardia, unstable congestive heart failure, active myocardial ischemia, or indwelling temporary pacemaker.
* Ventricular tachycardia or supraventricular tachycardia that requires treatment with class Ia antiarrhythmic drugs (e.g., quinidine, procainamide, disopyramide) or class III antiarrhythmic drug (e.g., sotalol, amiodarone, dofetilide). Use of other antiarrhythmic drugs is permitted.
* Second- or third-degree atrioventricular (AV) block unless treated with a permanent pacemaker.
* Complete left bundle branch block (LBBB) unless treated with a permanent pacemaker.
* Sensory or motor neuropathy \>= grade 2, according to Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0.
* Active seizure disorder uncontrolled by medication.
* Active or chronic infection requiring systemic therapy.
* Known homozygous DPD (dihydropyrimidine dehydrogenase) deficiency.
* Pregnancy or lactation at the time of randomization.
* Co-morbid illnesses or other concurrent disease that, in the judgement of the clinician obtaining informed consent, would make the patient inappropriate for entry into this study (i.e., unable to tolerate 6 months of combination chemotherapy or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens or prevent required follow-up).
* Prior testing with any available ctDNA test as part of the management of colon cancer, is not permitted.
