Clinical trial NCT04050345: Tracking Mutations in Cell Free Tumour DNA to Predict Relapse in Early Colorectal Cancer
Official title: Tracking Mutations in Cell Free Tumour DNA to Predict Relapse in Early Colorectal Cancer
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Colorectal Cancer
Lead sponsor: Royal Marsden NHS Foundation Trust
Sponsor class: OTHER
First posted: 2019-08-08
Enrollment: 1000
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
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,

Brief summary: 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: 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.

Eligibility criteria: 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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Primary outcomes:
measure: TRACC Part B (Translational sub study)
timeFrame: 6 years
measure: TRACC Part C (Randomised ctDNA guided adjuvant chemotherapy versus SoC study):
timeFrame: 4 years
Secondary outcomes:
measure: Relationship between ctDNA detection before, during and after treatment
timeFrame: 8 years
Other outcomes:
Locations:
city: Milton Keynes
country: United Kingdom
facility: Milton Keynes General Hospital
state: Buckinghamshire
city: Thornton Heath
country: United Kingdom
facility: Croydon University Hospital
state: Croydon
city: Dorchester
country: United Kingdom
facility: Dorset County Hospital NHS Foundation Trust
state: Dorset
city: Poole
country: United Kingdom
facility: Poole Hospital
state: Dorset
city: Chelmsford
country: United Kingdom
facility: Broomfield Hospital
state: Essex
city: Manchester
country: United Kingdom
facility: Christie NHS Foundation Trust
state: Greater Manchester
city: Portsmouth
country: United Kingdom
facility: Queen Alexandra Hospital
state: Hampshire
city: Wythenshawe
country: United Kingdom
facility: University Hospital of South Manchester & Manchester Royal Infirmary
state: Manchester
city: Taunton
country: United Kingdom
facility: Musgrove Park Hospital
state: Somerset
city: Weston-super-Mare
country: United Kingdom
facility: Weston General Hospital
state: Somerset
city: Carshalton
country: United Kingdom
facility: Epsom and St Helier's Hospitals NHS Trust
state: Surrey
city: Sutton
country: United Kingdom
facility: The Royal Marsden NHS Foundation Trust
state: Surrey
city: London
country: United Kingdom
facility: Guy's & St Thomas Hospital
state: UK
city: Bradford
country: United Kingdom
facility: Bradford Royal Infirmary
state: West Yorkshire
city: Salisbury
country: United Kingdom
facility: Salisbury District Hospital
state: Whiltshire
city: Aberdeen
country: United Kingdom
facility: Aberdeen Royal Infirmary
city: Aberystwyth
country: United Kingdom
facility: Bronglais Hospital
city: Aylesbury
country: United Kingdom
facility: Stoke Mandeville Hospital
city: Basildon
country: United Kingdom
facility: Basildon and Thurrock University Hospitals
city: Basingstoke
country: United Kingdom
facility: Basingstoke and North Hampshire Hospitals
city: Bedford
country: United Kingdom
facility: Bedford Hospital
city: Blackburn
country: United Kingdom
facility: Royal Blackburn Teaching Hospital
city: Boston
country: United Kingdom
facility: Pilgrim Hospital
city: Bournemouth
country: United Kingdom
facility: Royal Bournemouth Hospital
city: Bristol
country: United Kingdom
facility: University Hospitals Bristol NHS Foundation Trust
city: Burnley
country: United Kingdom
facility: Burnley General Teaching Hospital
city: Bury
country: United Kingdom
facility: West Suffolk Hospital
city: Cambridge
country: United Kingdom
facility: Addenbrookes Hospital
city: Canterbury
country: United Kingdom
facility: Kent and Canterbury Hospital
city: Carlisle
country: United Kingdom
facility: North Cumbria University Hospitals
city: Carmarthen
country: United Kingdom
facility: Glangwili Hospital
city: Cottingham
country: United Kingdom
facility: Castle Hill Hospital
city: Coventry
country: United Kingdom
facility: University Hospitals Coventry & Warwickshire
city: Crewe
country: United Kingdom
facility: Leighton Hospital
city: Crosshouse
country: United Kingdom
facility: University Hospital Crosshouse
city: Gillingham
country: United Kingdom
facility: Medway NHS Foundation Trust
city: Glasgow
country: United Kingdom
facility: Beatson West of Scotland Cancer Centre
city: Harlow
country: United Kingdom
facility: The Princess Alexandra Hospital NHS Trust
city: Haverfordwest
country: United Kingdom
facility: Withybush General Hospital
city: High Wycombe
country: United Kingdom
facility: Wycombe Hospital
city: Huddersfield
country: United Kingdom
facility: Calderdale and Huddersfield NHS Foundation Trust
city: Keighley
country: United Kingdom
facility: Airedale General Hospital
city: Kettering
country: United Kingdom
facility: Kettering General Hospital
city: Kingston Upon Thames
country: United Kingdom
facility: Kingston Hospital Foundation Trust
city: Larbert
country: United Kingdom
facility: Forth Valley Royal Hospital
city: Leeds
country: United Kingdom
facility: St James's University Hospital
city: Lincoln
country: United Kingdom
facility: Lincoln County Hospital
city: Llanelli
country: United Kingdom
facility: Prince Philip Hospital
city: London
country: United Kingdom
facility: Barts Health NHS Trust
city: London
country: United Kingdom
facility: North Middlesex University Hospital NHS Trust
city: London
country: United Kingdom
facility: Royal Free Hospital
city: London
country: United Kingdom
facility: St George's NHS Foundation Trust
city: London
country: United Kingdom
facility: The Royal Marsden NHS Foundation Trust - London
city: London
country: United Kingdom
facility: Chelsea and Westminster
city: Maidstone
country: United Kingdom
facility: Maidstone & Tunbridge Wells NHS Trust
city: Middlesex
country: United Kingdom
facility: Chase Farm Hospital
city: Northampton
country: United Kingdom
facility: Northampton General Hospital NHS Trust
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospital
city: Nuneaton
country: United Kingdom
facility: George Eliot Hospital
city: Preston
country: United Kingdom
facility: Royal Preston Hospital, Lancashire Teaching Hospitals
city: Romford
country: United Kingdom
facility: Barking Havering and Redbridge NHS Foundation Trust (Queen's Hospital
city: Sheffield
country: United Kingdom
facility: Weston Park Hospital
city: Shrewsbury
country: United Kingdom
facility: Royal Shrewsbury Hospital
city: South Shields
country: United Kingdom
facility: South Tyneside District Hospital
city: Southampton
country: United Kingdom
facility: University Hospital Southampton
city: Stockport
country: United Kingdom
facility: Stockport NHS Foundation Trust
city: Sunderland
country: United Kingdom
facility: Sunderland Royal Hospital
city: Sutton In Ashfield
country: United Kingdom
facility: King's Mill Hospital
city: Swansea
country: United Kingdom
facility: Singleton Hospital
city: Wigan
country: United Kingdom
facility: Wrightington, Wigan and Leigh NHS Foundation Trust
city: Winchester
country: United Kingdom
facility: Royal Hampshire County Hospital
Study officials:
affiliation: Royal Marsden NHS Foundation Trust
name: David Cunningham
role: STUDY_CHAIR
References: