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This Phase II/III trial will evaluate the what kind of chemotherapy to recommend to patients based on the presence or absences of circulating tumor DNA (ctDNA) after surgery for colon cancer.

Currently, there are no biomarkers validated prospectively in randomized studies for resected colon cancer to determine need for adjuvant chemotherapy. 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 colon cancer patients and may outperform traditional clinical and pathological features in prognosticating risk for recurrence. Colon cancer patients who do not have detectable ctDNA (ctDNA-) are at a much lower risk of recurrence and may not need adjuvant chemotherapy. Furthermore, for colon cancer pts with detectable ctDNA (ctDNA+) who are at a very high risk of recurrence, the optimal adjuvant chemotherapy 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 adjuvant chemotherapy.

Inclusion Criteria:

The patient must have an ECOG performance status of 0 or 1.

Patients must have histologically/pathologically confirmed Stage IIB, IIC, or Stage III

colon adenocarcinoma with R0 resection according to AJCC 8th edition criteria.

No radiographic evidence of overt metastatic disease within 45 days prior to Step 1/Study

entry (CT with IV contrast or MRI imaging is acceptable and must include chest, abdomen,

and pelvis).

The distal extent of the tumor must be greater than or equal to 12 cm from the anal verge

on colonoscopy or above the peritoneal reflection as documented during surgery or on

pathology specimen (i.e., excluding rectal adenocarcinomas warranting treatment with

chemoradiation).

The patient must have had an en bloc complete gross resection of tumor (curative

resection). 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.

The resected tumor specimen and a blood specimen from patients with Stage IIB, IIC, or

Stage III colon cancer must have central testing for ctDNA using the Signatera� assay by

Natera (after Step 1/Study entry and before Step2/Randomization). Patient must have

sufficient tissue to meet protocol requirements. This blood specimen for the Signatera

assay must be collected after surgery (and recommended at least 14 days post surgery).

Tumor must be documented as microsatellite stable or have intact mismatch repair proteins

through CLIA-approved laboratory testing. Patients whose tumors are MSI-H or dMMR are

excluded.

The treating investigator must deem the patient a candidate for all potential agents used

in this trial (5FU, LV, oxaliplatin and irinotecan).

The interval between surgery (post-operative Day 7) and Step 1/Study entry must be no

more than 60 days. NOTE: Step 1/Study Entry may occur as early as post operative Day 7,

but it cannot occur beyond 60 days from the actual date of the patient's surgery.

Availability and provision of adequate surgical tumor tissue for molecular diagnostics

and confirmatory profiling.

Adequate hematologic function within 28 days before Step 1/Study entry defined as

Follows:

• Absolute neutrophil count (ANC) must be greater than or equal to 1500/mm3;

• Participants with benign ethnic neutropenia (BEN): ANC less than 1300 mm3 are eligible.

• BEN (also known as constitutional neutropenia) is an inherited cause of mild or moderate neutropenia that is not associated with any increased risk for infections or other clinical manifestations. BEN is referred to as ethnic neutropenia because of its increased prevalence in people of African descent and other specific ethnic groups.

• Platelet count must be greater than or equal to 100,000/mm3; and

• Hemoglobin must be greater than or equal to 9 g/dL.

Adequate hepatic function within 28 days before Step 1/Study entry defined as follows:

• total bilirubin must be less than or equal to ULN (upper limit of normal) for the lab and

• alkaline phosphatase must be less than 2.5 x ULN for the lab; and

• AST and ALT must be less than 2.5 x ULN for the lab.

Adequate renal function within 28 days before Step 1/Study entry defined as serum

creatinine less than or equal to 1.5 x ULN for the lab or measured or calculated

creatinine clearance greater than or equal to 50 mL/min using the Cockroft-Gault formula

for patients with creatinine levels greater than 1.5 x ULN for the lab.

For Women Creatinine Clearance (mL/min) = (140 * age) x weight (kg) x 0.85 72 x serum

creatinine (mg/dL) For Men Creatinine Clearance (mL/min) = (140 * age) x weight (kg) 72 x

serum creatinine (mg/dL) NOTE: Adjusted body weight (AdjBW) should be used for patients

that have BMI greater than or equal to 28 (less than or equal to 30% above IBW).

HIV-infected patients on effective anti-retroviral therapy with undetectable viral load

within 6 months are eligible for this trial.

Pregnancy test (urine or serum according to institutional standard) done within 14 days

before Step 1/Study entry must be negative (for women of childbearing potential only).

Patients receiving a coumarin-derivative anticoagulant must agree to weekly monitoring of

INR if they are randomized to Arm 1 or Arm 3 and receive capecitabine.

Eligibility Criteria for Cohort A Arm-2 patients on Second Randomization

Patient must have developed a ctDNA +ve assay during serial monitoring.

Patient's willingness to be re-randomized affirmed.

The patient must continue to have an ECOG performance status of 0 or 1.

No radiographic evidence of overt metastatic disease.

Pregnancy test (urine or serum according to institutional standard) done within 14 days

before second randomization must be negative (for women of childbearing potential only).

Adequate hematologic function within 28 days before second randomization defined as

Follows:

• Absolute neutrophil count (ANC) must be greater than or equal to 1500/mm3;

• Participants with benign ethnic neutropenia (BEN): ANC less than 1300 mm3 are eligible.

• BEN (also known as constitutional neutropenia) is an inherited cause of mild or moderate neutropenia that is not associated with any increased risk for infections or other clinical manifestations. BEN is referred to as ethnic neutropenia because of its increased prevalence in people of African descent and other specific ethnic groups.

• Platelet count must be greater than or equal to 100,000/mm3; and

• Hemoglobin must be greater than or equal to 9 g/dL.

Adequate hepatic function within 28 days before second randomization defined as follows:

• total bilirubin must be less than or equal to ULN (upper limit of normal) for the lab and

• alkaline phosphatase must be less than 2.5 x ULN for the lab; and

• AST and ALT must be less than 2.5 x ULN for the lab.

Adequate renal function within 28 days before second randomization defined as serum

creatinine less than or equal to 1.5 x ULN for the lab or measured or calculated

creatinine clearance greater than or equal to 50 mL/min using the Cockroft-Gault formula

for patients with creatinine levels greater than 1.5 x ULN for the lab.

For Women Creatinine Clearance (mL/min) = (140 * age) x weight (kg) x 0.85 72 x serum

creatinine (mg/dL) For Men Creatinine Clearance (mL/min) = (140 * age) x weight (kg) 72 x

serum creatinine (mg/dL)

Exclusion Criteria:

Colon cancer histology other than adenocarcinoma (i.e., neuroendocrine carcinoma,

sarcoma, lymphoma, squamous cell carcinoma, etc.).

Pathologic, clinical, or radiologic overt evidence of metastatic disease. This includes

isolated, distant, or non-contiguous intra-abdominal metastases, even if resected.

Tumor-related bowel perforation.

History of prior invasive colon malignancy, regardless of disease-free interval.

History of bone marrow or solid organ transplantation (regardless of current

immunosuppressive therapy needs). Bone grafts, skin grafts, corneal transplants and

organ/tissue donation are not exclusionary.

Any prior systemic chemotherapy, targeted therapy, or immunotherapy; or radiation therapy

administered as treatment for colorectal cancer (e.g., primary colon adenocarcinomas for

which treatment with neoadjuvant chemotherapy and/or radiation is warranted are not

permitted). EXCEPTION: one cycle of chemotherapy (regimen per treating physicians'

discretion * 5-FU or capecitabine with or without oxaliplatin) is allowed but not

required after consent. The optional cycle of chemotherapy should be started greater than

or equal to 4 weeks from surgery and while awaiting Step 2 randomization.

Other invasive malignancy within 5 years before Step 1/Study entry. Exceptions are

colonic polyps, non-melanoma skin cancer or any carcinoma-in-situ.

Synchronous primary rectal and/ or colon cancers.

Patients with known history or current symptoms of cardiac disease, or history of

treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac

function using the New York Heart Association Functional Classification. To be eligible

for this trial, patients should be class 2B or better.

Sensory or motor neuropathy greater than or equal to grade 2, according to CTCAE v5.0.

Blood transfusion within two weeks before collection of blood for central ctDNA testing.

Active seizure disorder uncontrolled by medication.

Active or chronic infection requiring systemic therapy.

Known homozygous DPD (dihydropyrimidine dehydrogenase) deficiency.

Patients known to have Gilbert's Syndrome or homozygosity for UGT1A1*28 polymorphism.

Pregnancy or lactation at the time of Step 1/Study entry.

Co-morbid illnesses or other concurrent disease that 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).

Ineligibility Criteria for Cohort A Arm-2 patients on Second Randomization

Pregnancy or lactation at the time of randomization.

No longer a candidate for systemic chemotherapy (FOLFOX, CAPOX, and mFOLFIRINOX) in the

opinion of the treating investigator.