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

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)

Study Overview

• Status: Recruiting
• Conditions: Colorectal Cancer

Detailed Description

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.

• Study Type: Observational
• Enrollment (Estimated): 1000

Contacts and Locations

• Study Contact: Name: Annette Bryant; Phone Number: 4449 02086426011; Email: annette.bryant@rmh.nhs.uk
• Study Contact Backup: Name: Susie Slater, Dr; Email: Susanna.slater@rmh.nhs.uk

Study Locations

• United Kingdom
  • Basildon, United Kingdom
    • Recruiting
    • Basildon and Thurrock University Hospitals
    • Contact: Email: mse.clinicalresearch@nhs.net
    • Principal Investigator: Nadeem Ashraf
  • Basingstoke, United Kingdom
    • Recruiting
    • Basingstoke and North Hampshire Hospitals
    • Contact: research.team@hhft.nhs.uk
    • Principal Investigator: Francesco DiFabio
  • Bristol, United Kingdom
    • Recruiting
    • Bristol Haematology and Oncology Centre
    • Contact: Sophie Allen; Email: Sophie.Allen3@uhbw.nhs.uk
    • Principal Investigator: Stephen Falks
  • Carlisle, United Kingdom
    • Recruiting
    • North Cumbria University Hospitals
    • Contact: Email: research@ncic.nhs.uk
    • Principal Investigator: Sorena Afshar
  • Christchurch, United Kingdom, BH23 2JX
    • Recruiting
    • Royal Bournemouth Hospital
    • Principal Investigator: Bryony Eccles
    • Contact: Email: Hannah.Brennan@UHD.NHS.UK
  • Coventry, United Kingdom
    • Recruiting
    • Coventry and Warwickshire (
    • Contact: Email: linda.wimbush@uhcw.nhs.uk
    • Principal Investigator: Venessa Potter
  • Gillingham, United Kingdom
    • Recruiting
    • Medway Nhs Foundation Trust
    • Contact: Email: edyta.mccallum@nhs.net
  • Harlow, United Kingdom
    • Recruiting
    • The Princess Alexandra Hospital NHS Trust
    • Contact: Email: nooreen.badal@nhs.net
    • Principal Investigator: Venkatesh Gajapathy
  • Keighley, United Kingdom
    • Recruiting
    • Airedale General Hospital
    • Contact: Email: helen.henson@nhs.net
    • Principal Investigator: Shazza Rehman
  • Kingston Upon Thames, United Kingdom, KT27QB
    • Recruiting
    • Kingston Hospital Foundation Trust
    • Contact: Sheela Rao; Email: Sheela.rao@rmh.nhs.uk
    • Principal Investigator: Sheela Rao
  • London, United Kingdom, EC1M 6BQ
    • Recruiting
    • Barts Cancer Institute
    • Principal Investigator: Sarah Slater
  • London, United Kingdom, SW17 0QT
    • Recruiting
    • St George's NHS Foundation Trust
    • Contact: Mark Quarrell; Phone Number: 020 8725 3429 / 3569; Email: Mark.Quarrell@stgeorges.nhs.uk
    • Principal Investigator: Shreerang Bhide
  • London, United Kingdom
    • Recruiting
    • Chelsea and Westminster
    • Contact: Email: maria.elenanoval@nhs.net
    • Principal Investigator: Paris Tekkis
  • London, United Kingdom
    • Recruiting
    • North Middlesex University Hospital NHS Trust
    • Contact: Email: deborah.mccartney2@nhs.net
    • Principal Investigator: Lucinder Melcher
  • Maidstone, United Kingdom, ME16 9QQ
    • Recruiting
    • Maidstone Oncology Centre
    • Contact: Jeff Summers; Email: jeffsummers@nhs.net
    • Principal Investigator: Mark Hill
  • Northampton, United Kingdom, NN1 5BD
    • Recruiting
    • Northampton General Hospital NHS Trust
    • Contact: Trial Coordinator; Email: flora.gallamoza@nhs.net
    • Principal Investigator: Roshan Agarwal
  • Nottingham, United Kingdom
    • Recruiting
    • Nottingham University Hospital
    • Contact: Email: NCCTTGrp2@nuh.nhs.uk
    • Principal Investigator: Georgina Walker
  • Nuneaton, United Kingdom, CV10 7DJ
    • Recruiting
    • George Eliot Hospital
    • Contact: Nicola Whiehouse; Email: Nicola.whitehouse@geh.nhs.uk
    • Principal Investigator: Martin Scott-Brown
  • Preston, United Kingdom
    • Recruiting
    • Royal Preston Hospital, Lancashire Teaching Hospitals
    • Contact: Email: Research.Access@lthtr.nhs.uk
    • Principal Investigator: Deborah Willliamson
  • Romford, United Kingdom
    • Recruiting
    • Barking Havering and Redbridge NHS Foundation Trust (Queen's Hospital
    • Contact: Email: bhrut.development.research@nhs.net
    • Principal Investigator: Joseph Huang
  • South Shields, United Kingdom
    • Recruiting
    • South Tyneside and Sunderland NHS Foundation Trust
    • Contact: Email: stsft.research@nhs.net
    • Principal Investigator: Ashraf Azzabi
  • Stockport, United Kingdom
    • Recruiting
    • Stockport NHS Foundation Trust
    • Contact: Email: Research.Development@stockport.nhs.uk
    • Principal Investigator: Clare Hall
  • Wigan, United Kingdom
    • Recruiting
    • Wrightington, Wigan and Leigh NHS Foundation Trust
    • Contact: Email: oncologyresearch@wwl.nhs.uk
    • Principal Investigator: Kalena Marti
  • Winchester, United Kingdom
    • Recruiting
    • Royal Hampshire (Winchester)
    • Principal Investigator: Francesco DiFabio
    • Contact: Email: research.team@hhft.nhs.uk
  • Croydon
    • Thornton Heath, Croydon, United Kingdom, CR7 7YE
      • Recruiting
      • Croydon University Hospital
      • Contact: Muti Abulafi; Email: muti.abulafi@nhs.net
      • Contact: Ibiyemi Sadare; Email: ibiyemi.sadare@nhs.net
      • Principal Investigator: Muti Abulafi
  • Dorset
    • Dorchester, Dorset, United Kingdom, DT1 2JY
      • Recruiting
      • Dorset County Hospital NHS Foundation Trust
      • Principal Investigator: Brryony Eccles
    • Poole, Dorset, United Kingdom, BH15 2JB
      • Recruiting
      • Poole Hospital NHS Foundation Trust
      • Contact: Hannah Brennan; Email: Hannah.Brennan@UHD.NHS.UK
      • Principal Investigator: Bryony Eccles
  • England
    • London, England, United Kingdom, SE5 9NU
      • Recruiting
      • Cancer Research UK Clinical Groups at Guy's King's & St. Thomas' Hospitals
      • Contact: Paul Ross; Phone Number: 44-207-188-7188
  • Essex
    • Chelmsford, Essex, United Kingdom, CM1 7ET
      • Recruiting
      • Broomfield Hospital
      • Contact: Lorraine James; Email: Lorraine.James@meht.nhs.uk
      • Principal Investigator: Nicole George
  • Greater Manchester
    • Manchester, Greater Manchester, United Kingdom, M20 4BX
      • Recruiting
      • Christie NHS Foundation Trust
      • Contact: Stavroula Chalvatzi, Dr; Phone Number: +44(0)161 918 7907; Email: Stavroula.Chalvatzi@christie.nhs.uk
  • Manchester
    • Wythenshawe, Manchester, United Kingdom, M23 9LT
      • Recruiting
      • University Hospital of South Manchester & Manchester Royal Infirmary
      • Contact: Sarah Duff; Email: Sarah.Duff@UHSM.NHS.UK
      • Contact: Lindsay Piper; Email: Lindsay.Piper@UHSM.NHS.UK
      • Principal Investigator: Sarah Duff
  • Somerset
    • Taunton, Somerset, United Kingdom, TA1 5DA
      • Recruiting
      • Beacon Centre, Musgrove Park Hospital
      • Contact: Amanda McKenna; Email: Research@SomersetFT.nhs.uk
      • Principal Investigator: Gihan Ratmayake
  • Surrey
    • Carshalton, Surrey, United Kingdom, SM5 1AA
      • Recruiting
      • Epsom and St Helier's Hospitals NHS Trust
      • Principal Investigator: Nicholas West
      • Contact: Tiina Elonen; Email: tiina.elonen@nhs.net
    • Sutton, Surrey, United Kingdom, SM2 5PT
      • Recruiting
      • The Royal Marsden NHS Foundation Trust
      • Contact: Annette Bryant; Phone Number: 4449 02086426011; Email: annette.bryant@rmh.nhs.uk
      • Contact: Hsiang-Chi Chen; Phone Number: 3279 02086426011; Email: Hsiang-Chi.Chen@rmh.nhs.uk
      • Sub-Investigator: Susie Slater
  • UK
    • London, UK, United Kingdom, SE1 9RT
      • Recruiting
      • Guy's & St Thomas Hospital
      • Contact: Danielle Lyon; Email: danielle.lyon@gstt.nhs.uk
  • Whiltshire
    • Salisbury, Whiltshire, United Kingdom, SP2 8BJ
      • Recruiting
      • Salisbury District Hospital
      • Contact: Graham Branagan; Email: Graham.Branagan@salisbury.nhs.uk
      • Contact: Sofia Strong; Email: sophia.strong-sheldrake@nhs.net
      • Principal Investigator: Graham Branagan

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

TRACC Part B patients will have eligibility assessed, prior to surgery and again post-operatively with the histopathology report from surgery using the criteria below. Patients meeting the eligibility criteria at the first assessment will be registered. Rectal cancer patients that undergo pre-operative radiotherapy or chemo-radiotherapy have an additional eligibility assessment after treatment with the results of their imaging.

TRACC Part C: patients with histologically proven High risk Stage 2 or Stage 3 colon or rectal cancer, treated with curative surgery with no evidence of metastatic disease. Patients with histologically proven rectal cancer who have previously undergone neoadjuvant chemoradiotherapy are also eligible. Patients must be due to receive adjuvant chemotherapy,

Description

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:

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

4. 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
5. Absence of major post-operative complications or other clinical conditions that, in the opinion of the investigator, would 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 8 ± 2 weeks after surgery.
7. ECOG performance status 0- 2
8. 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

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Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort
Part B TRACC Colon; Patients with diagnosis of large bowel cancer (in the colon) and no evidence of metastatic disease
Part B TRACC Rectal; 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; 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; 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?

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

Collaborators and Investigators

• Sponsor: Royal Marsden NHS Foundation Trust
• Investigators: Study Chair: David Cunningham, Royal Marsden NHS Foundation Trust

Study record dates

Study Major Dates

• Study Start (Actual): December 5, 2016
• Primary Completion (Estimated): December 5, 2024
• Study Completion (Estimated): December 5, 2024

Study Registration Dates

• First Submitted: October 30, 2018
• First Submitted That Met QC Criteria: August 6, 2019
• First Posted (Actual): August 8, 2019

Study Record Updates

• Last Update Posted (Estimated): January 24, 2024
• Last Update Submitted That Met QC Criteria: January 23, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms
• Other Study ID Numbers: CCR4344

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No