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Tracking mutations in cell free tumour DNA to predict Relapse in Early Colorectal Cancer

Study ID: 47994
Short Title: TRACC C
Trust Name: HHFT,PHU,SFT,UHD
Recruitment Site: Basingstoke and North Hampshire Hospital,Poole Hospital,Queen Alexandra Hospital,Royal Bournemouth Hospital,Royal Hampshire County Hospital,Salisbury District Hospital
Disease Area: Colorectal cancer
Phase: N/A
Expected End Date: 31/01/2024
Postcode: RG24 9NA
SO22 5DG
PO6 3LY
SP2 8BJ
BH15 2JB
Contact Name: Amanda Pattie
Contact Email: studysupport1and3.crnwessex@nihr.ac.uk
Active: Yes

Eligibility criteria to be used prior to registration (for all patients, Part A and 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 lesions with high degree of suspicion on histology but not confirmed to be an adenocarcainoma and whose imaging is strongly suggestive of colorectal carcinoma (CRC) will be included. This patients 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 Additional eligibility criteria for rectal cancer patients following completion of pre-operative radiotherapy or chemoradiotherapy All patients proceeding to surgery Eligibility criteria at the first post-operative visit: Inclusion Criteria: • Stage I, II or III CRC based on the post-operative histopathology report • Availability of FFPE tumour tissue from surgery, for processing and analysis at the CMP For patients in the ctDNA guided interventional arm of the study only (Part C) Inclusion 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. Subjects must be due to receive adjuvant chemotherapy following surgery. Subjects with histologically proven stage III rectal cancer are eligible, including patients treated with neoadjuvant chemoradiotherapy (any T, N1 or N2, M0) with no evidence of metastatic disease. Subjects must be due to receive adjuvant chemotherapy following surgery. 3. Fully surgically resected tumour with clear resection margins (i.e., > 1 mm) 4. Patients must have detectable levels of ctDNA (i.e., ctDNA positive) in blood samples at baseline; this is collected pre-operatively if being treated with surgery alone, or before chemoradiotherapy in patients with locally advanced rectal cancer being treated with neoadjuvant chemoradiotherapy before surgery 5. 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 as calculated by Cockcroft and Gault equation (GFR ≥ 30ml/min if FOLFOX chemotherapy chosen and GFR ≥ 50ml/min if single agent capecitabine or CAPOX chosen) - Aspartate aminotransferase/ Alanine aminotransferase levels ≤ 2.5 upper limit of normal 6. Absence of major post-operative complications or other clinical conditions that, in the opinion of the investigator, would not contraindicate adjuvant chemotherapy 7. 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 after surgery. 8. ECOG performance status 0- 2 9. Able to give informed consent

Eligibility criteria to be used prior to registration (for all patients, Part A and 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. Additional eligibility criteria for rectal cancer patients following completion of pre-operative radiotherapy or chemoradiotherapy Patients scheduled to have further pre-operative treatment with chemotherapy • Patients that are no longer proceeding with surgery i.e. those in whom surgery is considered too high risk • Patients that are no longer proceeding with surgery as they are proceeding with a deferral of surgery approach Eligibility criteria at the first post-operative visit: Patients with no confirmed tissue diagnosis or high grade dysplasia included in the study based on imaging diagnosis but subsequent histopathology of surgical specimen confirms no carcinoma will be excluded • Scheduled to receive post-operative radiotherapy For patients in the ctDNA guided interventional arm of the study only (Part C) Exclusion Criteria: 1. History of concurrent and previous malignancy within the last 3 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, FOLFOX or single agent 5-FU or capecitabine) as stated in the SPC for each of the drugs

TRACC C is a prospective, randomised, multi-centre, study enrolling a total of 1681 patients Patients with high risk stage II or stage III colorectal cancer (CRC) whose pre-surgery blood test confirms presence of circulating tumour DNA (ctDNA) will be randomised to 1:1 with 810 patients treated in standard of care arm where patients are offered adjuvant chemotherapy according to national guidelines and 810 patients in the experimental arm, in which patients are treated based on ctDNA results . Patients will be stratified according to: 1. High risk stage II versus stage III 2. Site of primary tumour: right colon versus left colon versus rectum Hypothesis: ctDNA directed adjuvant chemotherapy administration will enable biomarker driven selection of patients who would benefit from adjuvant chemotherapy, thereby reducing the proportion of patients receiving adjuvant chemotherapy without compromising disease free survival. Background: There are 42,000 new cases of CRC, a top four cancer, diagnosed in the UK each year (CRUK Bowel Cancer Statistics, 2017). Approximately half of these cases are curable and include stage II (n= 9600/year) and III (n= 10,500/year). In patients with high risk stage II and stage III colorectal patients, adjuvant chemotherapy is currently determined by pathological features of the tumour resected at surgery. This is not a precise method of risk stratification of relapse and we are undoubtedly over-treating a proportion of patients already cured. Around 15-25% of patients offered standard oxaliplatin containing chemotherapy have permanent peripheral sensory neuropathy which can be quite debilitating and distressing (Grothey, Sem in Onc, 2003). Progress has been made in minimising unnecessary chemotherapy with the landmark UK-led publication (Iverson T et al, Lancet Onc, April 2018), confirmed by international meta-analyses (Grothey A et al, NEJM, March 2018) indicating that 3 months of post-operative chemotherapy was non-inferior to 6 months, without loss of benefit. The 3 year disease-free survival (DFS) in the 3-month group was 76.7% (95% CI 75.1–78.2) and in the 6-month group was 77.1% (75.6–78.6) [HR: 1.006 (0.909–1.114)]. The incidence of peripheral sensory neuropathy was of significantly less magnitude, with the rate being 58% in the 6 month group versus 25% in the 3 month group. The SCOT trial has changed clinical practice and our current standard of care is either 3 months of doublet capecitabine and oxaliplatin (CAPOX) or 6 months of single agent capecitabine chemotherapy in the adjuvant setting for patients with high risk stage II or stage III CRC. Liquid biopsies, in particular ctDNA, are emerging as an indicator of microscopic minimal residual disease following surgery. There is increasing evidence that postoperative ctDNA levels could potentially be a prognostic biomarker, identifying patients with high or low risk of recurrence. This represents the next step in individualising risk stratification and treatment minimisation, thereby truly delivering personalised care to patients. Multiple prospective studies have shown that time to recurrence, relapse free survival and overall survival were significantly shorter in patients who are ctDNA positive post-operatively compared to negative patients in stage II and stage III colon cancer (Tie et al., Science Translational Medicine, 2016; Diehn et al., ASCO 2017; Tie et al., ASCO 2018). Similarly, in patients with locally advanced rectal cancer (T3/T4 and/or N+) receiving chemo-radiotherapy recurrence-free survival was significantly worse in patients in whom ctDNA was detected after after surgery (HR 13.0; p< 0.001). (Tie et al., Gut Feb 2018). The technology for detecting ctDNA has advanced rapidly from the laborious droplet digital PCR (ddPCR) which involves designing individual probes for analysis, to next generation sequencing (NGS) directly in the blood by using suitable cutting edge gene panels. Our amendment now allows us to add TRACC C to the current TRACC protocol to use ctDNA analysis to guide therapy in high risk stage II and stage III patients with standard of care chemotherapy. This study will facilitate rapid implementation of this technology for assessment across the existing network of recruiting centres.

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