Tracking Mutations in Cell Free Tumour DNA to Predict Relapse in Early Colorectal Cancer

Study Overview
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Brief Summary
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TRACC Part B This is a multi-centre, prospective, translational research study involving the collection and analysis of tumour tissue, serial blood samples and clinical data in patients with newly diagnosed stage I, II and III CRC. TRACC Part C is a : (multi-centre, prospective, randomised study, of ctDNA guided adjuvant chemotherapy versus standard of care adjuvant chemotherapy study after curative surgery in patients with high risk stage II or stage III CRC. )It aims to demonstrate that a de-escalation strategy of ctDNA guided adjuvant chemotherapy is non- inferior to standard of care treatment as measured by 3 year disease free survival (DFS) in patients with high risk stage II or stage III colorectal cancer CRC with no evidence of minimal residual disease (MRD) (ctDNA negative)

Detailed Description
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TRACC Part B: Despite potentially curative surgery +/- adjuvant chemotherapy, a proportional of patients with early stage CRC will experience disease relapse. Current tools for surveillance, e.g., blood sampling for tumour markers (CEA) are neither sensitive nor specific. We hypothesise that detection of mutations in circulating free DNA (cfDNA) in plasma can predict relapse in patients with early stage CRC. Circulating cell free tumour DNA (ctDNA) maintains the same mutations that are present in tumour. In colorectal cancer CRC, primary tumours and& metastases exhibit high genomic concordance. Therefore the TRACC study TRACC Part B is investigating whether serial blood samples taken from in patients with stage II and III fully resected early stage CRC colorectal cancer that have undergone potentially curative surgery, blood samples to can be used to detect and& quantify ctDNA may in order to identify minimal residual disease MRD and predict relapse earlier than existing methods. CtDNA may ultimately help identify a subset of patients that are or are unlikely to benefit from adjuvant chemotherapy and could therefore safely spare some patients from receiving unnecessary chemotherapy & its associated side-effects. TRACC Part C: We hypothesis that ctDNA guided adjuvant chemotherapy administration will enable biomarker driven selection of patients who would and would not benefit from adjuvant chemotherapy and thereby reduce the proportion of patient receiving unnecessary adjuvant chemotherapy, reducing the potential side effects associated with it, but without compromising disease free survival (DFS). : This part of the study will use tThe blood test ctDNA result from a post-operative blood sample willto guide adjuvant chemotherapy treatment decisions. The study aims to demonstrate that athe de -escalation strategy of ctDNA guided adjuvant chemotherapy is non-inferior to standard of care treatment as measured by 3 year DFS in patients with high risk stage II and stage III CRC, in those who have no evidence of MRD (ctDNA negative). after surgery for patients with colorectal cancer who are following the standard of care pathway. Patients are randomised at the post- operative time point to: Arm A (standard of care adjuvant chemotherapy), or Arm B (ctDNA guided adjuvant chemotherapy) arm. For the ct DNA guided arm, patients who are ctDNA negative at this time point will have their chemotherapy de-escalated.

Official Title
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Tracking Mutations in Cell Free Tumour DNA to Predict Relapse in Early Colorectal Cancer

Conditions
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Colorectal Cancer

Participation Criteria
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Eligibility Criteria
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TRACC Part B Inclusion Criteria: New diagnosis of histologically confirmed CRC scheduled to undergo surgery with curative intent, with no radiological evidence of metastatic disease. Patients with high grade dysplasia whose imaging is suggestive of colorectal carcinoma (CRC) will be included but will be excluded post-surgery if carcinoma diagnosis is not confirmed Age≥18 Ability to give informed consent Able to adhere to follow up schedule TRACC Part B Exclusion Criteria: Scheduled to have neoadjuvant chemotherapy, (neoadjuvant chemoradiotherapy for patients with rectal cancer is permitted) Current or previous other malignancy within 5 years of study entry, except cured basal or squamous cell skin cancer, superficial bladder cancer, prostate intraepithelial neoplasm, carcinoma in situ of the cervix or other non-invasive malignancy TRACC Part C Inclusion Criteria: Subject ≥ 18 years of age 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, 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 after surgery or Subjects with histologically proven locally advanced stage III 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 after surgery Fully surgically resected tumour with clear resection margins (i.e., >1 mm). Adequate organ function Absolute neutrophil function ≥1.0 x 109/ L Platelet Count ≥ 75 x 109 / L Haemoglobin ≥80g/L (blood transfusion before randomisation is allowed) Adequate renal function (GFR ≥ 50ml/min if single agent capecitabine or CAPOX being administered) as calculated by Cockcroft and Gault equation Aspartate aminotransferase/ Alanine aminotransferase levels ≤ 2.5 upper limit of normal Absence of major post-operative complications or other clinical conditions that, in the opinion of the investigator, would contraindicate adjuvant chemotherapy 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 8 ± 2 weeks after surgery. ECOG performance status 0- 2 Able to give informed consent TRACC Part C Exclusion criteria 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 single agent capecitabine) as stated in the SmPC for each of the drugs 5. Subjects due to receive 5-Flurouracil (5-FU) based adjuvant chemotherapy (either single agent 5-FU or in combination with oxaliplatin) will not be eligible for Part C of the study -

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Part B TRACC Colon<br>Patients with diagnosis of large bowel cancer (in the colon) and no evidence of metastatic disease | |
| Part B TRACC Rectal<br>Patients who have a diagnosis of large bowel cancer (in the Rectum) and no evidence of metastatic disease | |
| Part C TRACC- Standard of Care Adjuvant Chemotherapy<br>Randomised to Arm A: Standard of Care Arm (Patients with fully resected high risk stage II or stage III colon or Rectal cancer with no evidence of metastatic disease. Patients with locally advanced rectal cancer who have previously undergone chemoradiotherapy are also eligible to enrol. | |
| Part C-ct DNA Guided Arm<br>Patients with fully resected high risk stage II or stage III colon or rectal cancer with no evidence of metastatic disease. Patients with locally advanced rectal cancer who have previously undergone chemoradiotherapy are also eligible to enrol. De-escalation of adjuvant chemotherapy in patients who have a post-operative ctDNA negative result | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| TRACC Part B (Translational sub study) | • To assess whether detection of ctDNA predicts for relapse in patients with stage II and III colorectal cancer (CRC) that have undergone surgery with curative intent | 6 years | 
| TRACC Part C (Randomised ctDNA guided adjuvant chemotherapy versus SoC study): | • To demonstrate de-escalation strategy of ctDNA guided adjuvant chemotherapy is non- inferior to standard of care treatment as measured by 3 year disease free survival in patients with high risk stage II or stage III colorectal cancer with no evidence of minimal residual disease (ctDNA negative) | 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relationship between ctDNA detection before, during and after treatment | To calculate the association between detectable ctDNA with disease free survival and overall survival at four time points during treatment. | 8 years |