Identification and Treatment Of Micrometastatic Disease in Stage III Colon Cancer

Inclusion Criteria:

* Participants must have histologically confirmed resected Stage III adenocarcinoma of the colon. Any T \[Tx, T1, T2, T3, or T4-\], N1-2M0.
* Participants must have completely resected disease. In patients with tumor adherent to adjacent structures, en block RO resection must be documented.
* Entire tumor must be in the colon (rectal involvement is excluded).
* Participants must have completed standard adjuvant chemotherapy per the discretion of the treating physician. Standard therapy includes FOLFOX, CAPOX, or therapy with 5FU analog alone will be permitted if it constitutes appropriate standard therapy in the opinion of the treating physician.
* Participants must not have received prior neoadjuvant chemotherapy.
* Age ≥18 years.
* ECOG performance status ≤1.
* Life expectancy of greater than 3 months.
* Participants must have normal organ and marrow function as defined below:

  * leukocytes ≥3,000/mcL
  * absolute neutrophil count ≥1,500/mcL
  * platelets ≥100,000/ mcL
  * total bilirubin within normal institutional limits. For patients with Gilbert's syndrome, total bilirubin must be ≤ 2 and documented as elevated indirect bilirubin.
  * AST(SGOT)/ALT(SGPT) ≤3 (AST) or ≤ 3 (ALT) × institutional upper limit of normal
  * creatinine within normal institutional limits OR
  * creatinine clearance ≥40 mL/min/1.73 m2 for participants with creatinine levels above institutional normal by Cockroft-Gault formula.
* In order to be eligible for the ctDNA positive cohort, women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG).
* The effects on the developing human fetus are unknown. For this reason and because 5FU, Capecitabine, Oxaliplatin, Irinotecan, Leucovorin, Nivolumab, and Cetuximab are known to be teratogenic, in order to be eligible for the ctDNA positive cohort, females of child-bearing potential (FOCBP) and males must be willing to abstain from heterosexual activity or use 2 forms of effective contraception (fail rate of less than 1% per year, hormonal or barrier method of birth control) from time of informed consent until 5 months (FOCBP) and 7 months (males) after the last dose of study treatment. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Women who are not of childbearing potential, ie, who are postmenopausal or surgically sterile as well as azoospermic men, do not require contraception.
* Participants must have documentation of microsatellite instability status. Testing by NGS, PCR based assessment and Immunohistochemistry (IHC) are acceptable. Presence of deficient (d) DNA mismatch repair (dMMR) may be assessed by IHC for MMR protein expression (MLH1, MSH2, MSH6, PMS2) where loss of one or more proteins indicated dMMR. This may be done locally.
* Participant's circulating tumor DNA (ctDNA) assay (Guardant Reveal-Guardant Health) must satisfy assay specific quality control metrics to generate a result.
* In order to be eligible for the ctDNA positive cohort, patient must be ctDNA positive following adjuvant therapy using the CLIA certified Guardant Reveal assay. ctDNA positive will be defined as positive based on having a tumor derived signal in the cfDNA that passes calling threshold ("ctDNA detected").
* Ability to understand and the willingness to sign a written informed consent document.

Trastuzumab and Pertuzumab Specific Inclusion Criteria for HER2 cohort

* HER2 overexpression/amplification as shown by NGS sequencing, IHC/FISH or Tumor with 3+ by IHC or 2+ by IHC and HER2/cep17 ratio \>2 by FISH.
* AST(SGOT) ≤ 1.25 and ALT(SGPT) ≤ 1.25 × institutional upper limit of normal
* Participants of childbearing potential must use effective contraceptive methods during and for 7 months after the last dose of HER2-targeted therapy
* History of other malignancies within the 5 years prior to study registration, except for the following: carcinoma in situ of the cervix, carcinoma in situ of the colon, melanoma in situ, and basal cell and squamous cell carcinomas of the skin (\*malignancies occurring more than 5 years prior to study entry are permitted if curatively treated with surgery alone).
* LVEF ≥ 55% measured by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) within 12 weeks of treatment start.

Exclusion Criteria:

* Patients who are receiving additional investigational therapy or on another investigational protocol
* Patients who have confirmed metastatic disease per CT.
* Patients who are unable to get any standard adjuvant therapy
* Patients who have received more than 6 months of standard adjuvant therapy at the time of study entry.
* With the exception of standard of care adjuvant therapy, patient received anticancer therapy including chemotherapy, immunotherapy, or antineoplastic biologic therapy (e.g., cetuximab, bevacizumab etc.), within 30 days prior to start of study treatment.
* Patients who are MSI-high or have a BRAF V600E mutation are excluded from Arm 1 (FOLFIRI) and Arm 2 (Active Surveillance).
* Patients with a BRAFV600E mutation and who are MSI-high are excluded from Arm 5 (ENCO/BINI/CETUX).
* Has uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
* Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
* (ctDNA positive cohort only). Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 6 months for woman and 6 months for men, after the last dose of trial treatment.
* Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin and squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
* Has an active infection requiring systemic therapy.

Nivolumab Specific Inclusion Criteria for MSI-H Cohort:

* Must have documentation of microsatellite instability status. NGS, PCR based assessment and Immunohistochemistry (IHC) are acceptable. Presence of deficient (d) DNA mismatch repair (dMMR) may be assessed by IHC for MMR protein expression (MLH1, MSH2, MSH6, PMS2) where loss of one or more proteins indicated dMMR. This may be done locally.
* Patients must have detectable ctDNA (Guardant Reveal assay) post standard adjuvant therapy in order to be in this cohort.

Nivolumab Specific Exclusion Criteria for MSI-H Cohort:

* Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other forms of immunosuppressive therapy within 7 days prior to the first dose of nivolumab treatment. Subject requiring systemic steroids are excluded from the trial. The use of physiologic doses of corticosteroids may be approved after discussion with the sponsor.
* Has a known history of active TB (Bacillus tuberculosis)
* Hypersensitivity to nivolumab or any of is excipients
* Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
* Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
* Patients that require supplemental oxygen are excluded.
* Patients who are known HIV+ positive are eligible if their CD4+ count is ≥ 350/μL for at least 3 months and they have an undetectable viral load. In addition, patient must be currently receiving Highly Active Antiretroviral Therapy (HAART) and have been on therapy for at least 3 months prior to study entry, under the care of an Infectious Diseases specialist. Patients should have no history of an AIDS-defining opportunistic infection.
* Patients known hepatitis B and hepatitis C must be under the care of viral hepatitis expert consultant. Patients with hepatitis B are required to be treated with anti-HBV treatment (e.g., entecavir) and have an HBV viral load \<100 IU/mL. Patients with hepatitis C need to have received prior and/or ongoing hepatitis C treatment.
* Has received a live vaccine within 30 days of planned start of study therapy. Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.

Encorafenib, binimetinib, and cetuximab Specific Inclusion Criteria for BRAF mutant Cohort

* Presence of BRAFV600E in tumor tissue previously determined by IMPACT at any time prior to Screening.
* Patients must have detectable ctDNA (Guardant Health LUNAR assay) post standard adjuvant therapy in order to be in this cohort.
* Participants must have normal organ, marrow, and hematologic function as defined below:

  * Hemoglobin ≥9 g/dL (5.58 mmol/L)
  * Total bilirubin ≤ 1.5 (25.65 μmol/L)
  * Platelets ≥100,000/μL

Encorafenib, binimetinib, and cetuximab Specific Exclusion Criteria for BRAF V600E mutant Cohort:

* Patients with a BRAFV600E mutation and who are MSI-H are excluded from Arm 5 (ENCO/BINI/CETUX)
* Prior therapy with a BRAF inhibitor (e.g., encorafenib, dabrafenib, vemurafenib) and/or a MEK inhibitor (e.g., binimetinib, trametinib, cobimetinib).
* Known hypersensitivity or contraindication to any component of binimetinib or encorafenib or their excipients.
* The patient has a history of allergic reactions attributed to compounds of chemical or biologic composition similar to those of cetuximab, or has red meat allergy or tick bit history.
* Inability to swallow and retain study drug.
* Participants who have undergone major surgery (e.g., in-patient procedures) ≤ 6 weeks prior to start of study treatment or who have not recovered from side effects of such procedure.
* Participants who have had radiotherapy ≤ 14 days prior to start of study treatment or who have not recovered from side effects of such procedure. Note: Palliative radiation therapy must be complete 7 days prior to the first dose of study treatment.
* Patient has not recovered to ≤ Grade 1 from toxic effects of prior therapy before starting study treatment.

Note: Stable chronic conditions (≤ Grade 2) that are not expected to resolve (such as neuropathy, myalgia, alopecia, prior therapy-related endocrinopathies) are exceptions and may enroll.

* Impaired cardiovascular function or clinically significant cardiovascular disease including, but not limited to, any of the following:

  * History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty or stenting) \< 6 months prior to Screening;
  * Congestive heart failure requiring treatment (New York Heart Association Grade ≥ 2);
  * Left ventricular ejection fraction (LVEF) \< 50% as determined by MUGA or ECHO;
  * Uncontrolled hypertension defined as persistent systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg despite current therapy;
  * History or presence of clinically significant cardiac arrhythmias (including resting bradycardia, uncontrolled atrial fibrillation or uncontrolled paroxysmal supraventricular tachycardia);
  * Triplicate average baseline QTc interval ≥ 480 ms.
* Impairment of gastrointestinal function or disease which may significantly alter the absorption of study drug (e.g., active ulcerative disease, uncontrolled vomiting or diarrhea, malabsorption syndrome, small bowel resection with decreased intestinal absorption), or recent (≤ 3 months) history of a partial or complete bowel obstruction, or other conditions that will interfere significantly with the absorption of oral drugs.
* Known history of acute or chronic pancreatitis.
* Concurrent neuromuscular disorder that is associated with elevated CK (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy).
* History or current evidence of RVO or current risk factors for RVO (e.g., uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes); history of retinal degenerative disease.
* Current use of a prohibited medication (including herbal medications, supplements, or foods), as described in Section 5.5, or use of a prohibited medication ≤ 1 week prior to the start of study treatment.
* History of thromboembolic or cerebrovascular events ≤ 12 weeks prior to the first dose of study treatment. Examples include transient ischemic attacks, cerebrovascular accidents, hemodynamically significant (i.e. massive or sub-massive) deep vein thrombosis or pulmonary emboli.

Note: Patients with either deep vein thrombosis or pulmonary emboli that does not result in hemodynamic instability are allowed to enroll as long as they are on a stable dose of anticoagulants for at least 4 weeks.

Note: Patients with thromboembolic events related to indwelling catheters or other procedures may be enrolled.

* Concurrent or previous other malignancy within 2 years of study entry, except adequately treated basal or squamous cell skin cancer, prostate intraepithelial neoplasm, carcinoma in-situ of the cervix, Bowen's disease and Gleason 6 prostate cancer.
* Known history of positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
* Evidence of Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV) infection. Note: Patients with laboratory evidence of cleared HBV or HCV infection may be enrolled.

Note: Patients with no prior history of HBV infection who have been vaccinated against HBV and who have a positive antibody against hepatitis B surface antigen as the only evidence of prior exposure may be enrolled.

Trastuzumab and Pertuzumab Specific Exclusion Criteria for HER2 cohort

* Serious cardiac illness or medical conditions including but not confined to:

  * History of NCI CTCAE v5.0 Grade ≥ 3 symptomatic congestive heart failure (CHF) or New York Heart Association (NYHA) Class ≥ II
  * High-risk uncontrolled arrhythmias ie, atrial tachycardia with a heart rate ≥ 100/min at rest, significant ventricular arrhythmia (ventricular tachycardia) or higher-grade AV-block (second degree AV-block Type 2 \[Mobitz 2\] or third degree AV-block)
  * Serious cardiac arrhythmia or severe conduction abnormality not controlled by adequate medication
  * Angina pectoris requiring anti-anginal medication.
  * Evidence of myocardial infarction within 12 months prior to enrollment
  * Clinically significant valvular heart disease
  * Evidence of transmural infarction on electrocardiogram (ECG)
  * Poorly controlled hypertension (eg, systolic \> 180 mm Hg or diastolic \> 100 mm Hg).
  * History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias, such as structural heart disease (e.g., severe left ventricular systolic dysfunction \[LVSD\], left ventricular hypertrophy), coronary heart disease (symptomatic or with ischemia demonstrated by diagnostic testing), clinically significant electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia, hypocalcemia), or family history of sudden unexplained death or long QT syndrome
* High risk patients who have received chemoprevention drugs in the past are not allowed to enroll in the study.
* Concurrent anti-cancer treatment in another investigational trial, including hormone therapy, bisphosphonate therapy and immunotherapy.
* Other concurrent serious diseases that may interfere with planned treatment including severe pulmonary conditions/illness (e.g., infections or poorly controlled diabetes).