Table 1 TRACC Part C eligibility criteria

1. Subject ≥ 18 years of age

2. Subjects with histologically proven high-risk stage II or stage III colon or rectal cancer treated with curative intent with surgery alone (any T, N1 or N2) with no evidence of metastatic disease. High-risk stage II is defined as having one or more of the following: T4 disease, tumour obstruction and/or perforation of the primary tumour during the pre-operative period, inadequate nodal harvest as indicated by < 12 nodes examined, poorly differentiated grade on histology, perineural invasion, peritoneal involvement or extramural venous/lymphatic invasion. Subjects must be due to receive adjuvant chemotherapy following surgery

Subjects with histologically proven locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy (any T, N1 or N2, M0) with no evidence of metastatic disease are eligible. Subjects must be due to receive adjuvant chemotherapy following surgery

3. Fully surgically resected tumour (R0) with clear resection margins (i.e., > 1 mm)

4. Adequate organ function

- Absolute neutrophil function ≥ 1.0 × 10⁹/ L

- Platelet Count ≥ 75 × 10⁹ / L

- Haemoglobin ≥ 80 g/L (blood transfusion before randomisation is allowed)

- Adequate renal function as calculated by Cockcroft and Gault equation (GFR ≥ 50 ml/min if single agent capecitabine or CAPOX being administered)

- Aspartate aminotransferase/ Alanine aminotransferase levels ≤ 2.5 upper limit of normal

5. Absence of major post-operative complications or other clinical conditions that, in the opinion of the investigator, would not contraindicate adjuvant chemotherapy

6. Patients should be assessed by Oncology team for suitability and assessment for adjuvant chemotherapy, be able to have post-operative ctDNA sample collected and be randomised by week 4–8 (± 2 weeks) after surgery and commence adjuvant chemotherapy within 12 weeks after surgery

7. ECOG performance status 0- 2

8. Able to give informed consent

1. History of concurrent and previous malignancy within the last 5 years, with the exception of non- melanomatous skin cancer and carcinoma in situ

2. Any major post-operative complications or other clinical conditions that in the opinion of the investigator would contra-indicate adjuvant chemotherapy

3. Any subject not due to receive adjuvant chemotherapy will not be eligible for Part C of the study

4. Hypersensitivity or contraindication to the drug(s) associated with the planned choice of systemic chemotherapy (CAPOX or capecitabine) as stated in the Summary of Product Characteristics (SmPC) for each of the drugs

5. Subjects due to receive 5-flurouracil (5FU) based adjuvant chemotherapy (either single agent 5FU or in combination with oxaliplatin) will not be eligible for Part C of the study, these patients will continue to be followed in the observational Part B of the study