Clinical Trials

Inclusion Criteria:

• The patient must have signed and dated an IRB-approved consent form that conforms to federal and institutional guidelines.
• The patient must be ≥ 18 years old.
• The patient must have an ECOG performance status of 0 or 1.
• Patients must have histologically/pathologically confirmed Stage IIIA or Stage IIIB colon adenocarcinoma (T1-3, N1/N1c) with R0 resection accordingly to AJCC 8th edition criteria.
  • NOTE: Patients with pathologic stages II or IIIC colon adenocarcinoma with R0 resection who have a commercially obtained Signatera™ ctDNA+ve assay result post-operatively meeting all timelines and eligibility requirements otherwise, are eligible for enrollment and inclusion in Cohort B.
• No radiographic evidence of overt metastatic disease within 28 days prior to 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 ≥ 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 IIIA or Stage IIIB colon cancer must have central testing for ctDNA using the Signatera™ assay by Natera.
  • NOTE: Patients with stage IIIA or IIIB colon cancer who otherwise meet eligibility criteria and have had ctDNA status checked with the Signatera™ assay as routine care outside of the study, are allowed to be enrolled, and will be retested and placed in either Cohort A or Cohort B depending on the central ctDNA testing result.
  • NOTE: Patients with stage II or IIIC colon cancer who otherwise meet eligibility criteria and have had ctDNA status checked with the Signatera™ assay as routine care outside of the study AND have a ctDNA+ve result, are allowed to be enrolled. Patients will have central ctDNA testing, confirmed to be ctDNA+ve, and placed in Cohort B.
• 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 study entry must be no more than 60 days.
• Availability and provision of adequate surgical tumor tissue for molecular diagnostics and confirmatory profiling.
• Adequate hematologic function within 28 days before study entry defined as follows:
  • Absolute neutrophil count (ANC) must be ≥ 1500/mm^3;
  • Platelet count must be ≥ 100,000/mm^3; and
  • Hemoglobin must be ≥ 9 g/dL;
• Adequate hepatic function within 28 days before study entry defined as follows:
  • Total bilirubin must be ≤ ULN (upper limit of normal) for the lab; and
  • Alkaline phosphatase must be < 2.5 x ULN for the lab; and
  • AST and ALT must be < 2.5 x ULN for the lab.
• Adequate renal function within 28 days before study entry defined as serum creatinine ≤ 1.5 x ULN for the lab or measured or calculated creatinine clearance ≥ 50 mL/min using the CockroftGault formula for patients with creatinine levels > 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).
• 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 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.

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).
• Other invasive malignancy within 5 years before 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 ≥ 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 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).

Inclusion 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 ≥ 1500/mm^3;
  • Platelet count must be ≥ 100,000/mm^3; and
  • Hemoglobin must be ≥ 9 g/dL.
• Adequate hepatic function within 28 days before second randomization defined as follows:
  • Total bilirubin must be ≤ ULN (upper limit of normal) for the lab; and
  • Alkaline phosphatase must be < 2.5 x ULN for the lab; and
  • AST and ALT must be < 2.5 x ULN for the lab.
• Adequate renal function within 28 days before second randomization defined as serum creatinine ≤ 1.5 x ULN for the lab or measured or calculated creatinine clearance ≥ 50 mL/min using the Cockroft-Gault formula for patients with creatinine levels > 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 for Cohort A - Arm 2 patients on Second Randomization:

• Pregnancy or lactation at the time of second randomization.
• No longer a candidate for systemic chemotherapy (FOLFOX, CAPOX, and mFOLFIRINOX) in the opinion of the treating investigator.

Eligibility last updated 5/26/22. Questions regarding updates should be directed to the study team contact.