Neoplasms

Digestive System Diseases

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Rectal Neoplasms

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Intestinal Diseases

Rectal Diseases

Management according to national guidelines - conventional MDT, clinical assessment post-treatment planning

mrTRG directed management 'Good response' (mrTRG 1\&2) - deferral of surgery (watch \& wait) offered. 'Poor response' (mrTRG 3-5) - local colorectal MDT is informed and uses information to discuss and agree next steps in treatment and surveillance.

MRI reporting of tumour but not mrTRG in the control arm = standard of care

High resolution MRI scan

Watch and wait offered for good responders Consider further treatment for poor responders

mrTRG assessment

Caroline Martin

Syvella Ellis

Angela Cheyne

Sue Rodwell

Megan Topping

Caroline Palmer

Brendan Moran, MD

Mit Dattani, MD

Katrina Parkinson

Angela Peake

Sophia Strong-Sheldrake

Julie Attlee

Graham Branagan, MD

Alaaeldin Shablak, MD

Robert Hollister

Stephen Falk, MD

Lucy Thorogood

Celine Driscoll

Bruce Sizer, MD

Louise Devlin

Angela Scullion

Cindy Chew, MD

Jonathan Hatton

Rajarshi Roy, MD

Helen Wilson

Lynda Poole

David Wilson, MD

Cordelia Grant

Sheela Rao, MD

Gina Brown, MD

Open to patients undergoing any pre-operative treatment for locally advanced rectal cancer, TRIGGER is the only phase III clinical trial in the UK offering watch and wait. All patients will have post treatment MRI scans routinely performed, no change from the MERCURY trials high resolution MRI protocol is required. Patients will be randomised to either the control arm for management according to national guidelines - conventional MDT, clinical assessment post-treatment planning using the baseline MRI. Patients in the interventional arm will have their post treatment MRI scans read by a radiologist trained and supported to reliably report the mrTRG grade and have their management directed accordingly - 'Good response' (mrTRG 1\&2) - watch and wait (avoidance of surgery) offered. 'Poor response' (mrTRG 3-5) - local colorectal MDT is informed and uses information to discuss and agree next steps in treatment and surveillance. Patients are followed up for five years with QoL questionnaires completed at registration, 3 and 5 years.

The only phase III clinical trial in the UK offering watch and wait, the TRIGGER trial aims to validate mrTRG as an imaging biomarker for the stratified management of patients with locally advanced rectal cancer. The 'good responders' (mrTRG1\&2) often have no evidence of tumour and it may be possible to avoid surgery in this group and so maintaining QoL while not impacting survival rates. The 'poor responders' (mrTRG3-5) are at high risk of poor oncological outcomes and this knowledge is useful in planning ongoing treatment and surveillance.

TRIGGER is now a non-cTIMP trial as the protocol does not specify chemotherapy or IMP treatments. Decisions about the use of chemotherapy will be based upon local MDT discussions as is normal practice and national policy and the trial CRFs will capture these decisions and whether more treatment is given to patients or not. TRIGGER does not mandate or recommend the use of any treatments: specifically it does not suggest the use of investigational medicinal products. If any centre wishes to use IMPs this would be in the context of separate trial protocols and would not preclude entry into TRIGGER.

Magnetic Resonance Tumour Regression Grade (mrTRG) as a Novel Biomarker - Phase III Non CTIMP Trial

Magnetic Resonance Tumour Regression Grade (mrTRG) as a Novel Biomarker to Stratify Management of Good and Poor Responders to Radiotherapy: A Rectal Cancer Multicentre Randomised Control Trial to Avoid Surgery With 'Watch and Wait' or Intensify Treatment According to mrTRG

Non-inferiority of overall survival at 3 years for the mrTRG (MRI Tumour Regression Grade) good response group (mrTRG 1 and 2) compared with control.

Correlation of baseline and post treatment prognostic factors on imaging and pathology against survival outcomes

Agreement between local and centrally measured mrTRG (MRI Tumour Regression Grade) (mrTRG 1 good to mrTRG 5 poor)

Comparison by arm of early (30 day) surgical morbidity according to the Clavien-Dindo classification.

Comparison by arm of late (up to 12 months) surgical morbidity according to the Clavien-Dindo classification.

Reporting of treatment given against measurement of mrTRG (MRI Tumour Regression Grade) response (mrTRG 1 good to mrTRG 5 poor)

Reporting of treatment given survival outcomes

Quality of life assessed using EORTC QLQ-C30, EQ-5D and Low Anterior Resection Syndrome Score (LARS).scans performed at baseline, post-CRT and during surveillance schedule.

Healthcare costs using NHS Reference Costs combined with health resource utilization and QoL data

Correlate molecular and immunological biomarkers with outcome measures of mrTRG (MRI Tumour Regression Grade) response, (mrTRG 1 good to mrTRG 5 poor) and survival outcomes

Correlate ctDNA levels with outcome measures of mrTRG (MRI Tumour Regression Grade) (mrTRG 1 good to mrTRG 5 poor) and survival outcomes

Spots Global Cancer Trial Database for high resolution mri scan