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Evaluating chemotherapy based on circulating tumor DNA in colon cancer patients

Colon Adjuvant Chemotherapy Based on Evaluation of Residual Disease

Phase2; Phase3 Interventional NRG Oncology · NCT05174169

This study is testing if checking for tumor DNA in the blood after surgery can help doctors decide the best chemotherapy for people with Stage III colon cancer.

Quick facts

PhasePhase2; Phase3
Study typeInterventional
Enrollment1912 (estimated)
Ages18 Years and up
SexAll
SponsorNRG Oncology Academic / other
Drugs / interventionschemotherapy, immunotherapy, radiation
Locations1056 sites (Birmingham, Alabama and 1055 other locations)
Trial IDNCT05174169 on ClinicalTrials.gov

What this trial studies

This Phase II/III trial aims to determine the appropriate chemotherapy regimen for patients with Stage III colon cancer based on the presence or absence of circulating tumor DNA (ctDNA) after surgical resection. The study will assess whether patients with undetectable ctDNA are at a lower risk of recurrence and may not require adjuvant chemotherapy, while those with detectable ctDNA will be evaluated for optimal chemotherapy options. By using ctDNA as a biomarker, the trial seeks to improve risk stratification and treatment decisions for colon cancer patients.

Who should consider this trial

Good fit: Ideal candidates include patients with histologically confirmed Stage IIB, IIC, or Stage III colon adenocarcinoma who have undergone complete surgical resection.

Not a fit: Patients with overt metastatic disease or those with rectal adenocarcinomas requiring chemoradiation may not benefit from this study.

Why it matters

Potential benefit: If successful, this approach could lead to more personalized treatment plans, potentially reducing unnecessary chemotherapy for some patients and improving outcomes for those at higher risk of recurrence.

How similar studies have performed: Other studies have shown promise in using ctDNA for risk stratification in various cancers, suggesting that this approach may be beneficial in colon cancer as well.

Eligibility criteria

Show full inclusion / exclusion criteria 
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.

Where this trial is running

Birmingham, Alabama and 1055 other locations

+1006 more sites — see ClinicalTrials.gov for the full list.

Study contacts

How to participate

  1. Review the eligibility criteria above with your treating physician.
  2. Visit the official trial page on ClinicalTrials.gov for the most current contact information and recruitment status.
  3. Contact the listed study coordinator or principal investigator to request pre-screening. Pre-screening is free and never obligates you to enroll.
View on ClinicalTrials.gov → Find more trials like this →
Conditions Stage III Colon CancerctDNA positivectDNA negativeAdjuvant ChemotherapyNateraSignateramFOLFOX6Stage III
Last reviewed 2026-06-13 by the Find a Trial editorial team. Information on this page is for educational purposes and is not medical advice. Always consult qualified healthcare professionals about clinical trial participation.