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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Rectal Cancer

Intervention / Treatment
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* Diagnostic Test: High resolution MRI scan
* Diagnostic Test: mrTRG assessment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: MRI defined locally advanced rectal carcinoma i.e. one or more: greater than or equal to mrT3c; mrEMVI positive; mr N1c; mr CRM positive Biopsy confirmed adenocarcinoma of radiologically defined rectum Be deemed to require preoperative chemoradiotherapy (CRT) or total neoadjuvant therapy (TNT) Exclusion Criteria: Metastatic disease MRI, radiotherapy and/or chemotherapy contraindications A post-treatment MRI performed more than 10 weeks after the completion of radiotherapy if given Previous malignancy within preceding 5 years if risk of recurrence >5%

Ages Eligible for Study
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Minimum Age: 16 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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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Control arm<br>Management according to national guidelines - conventional MDT, clinical assessment post-treatment planning | Diagnostic Test: High resolution MRI scan<br>* MRI reporting of tumour but not mrTRG in the control arm = standard of care<br>|
| Experimental: Intervention arm<br>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. | Diagnostic Test: High resolution MRI scan<br>* MRI reporting of tumour but not mrTRG in the control arm = standard of care<br>Diagnostic Test: mrTRG assessment<br>* Watch and wait offered for good responders Consider further treatment for poor responders<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To show that patients can successfully avoid surgery after achieving a good response to treatment as measured on MRI (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. | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To describe the prognostic features associated with good and poor response to treatment as measured by MRI (mrTRG) | Correlation of baseline and post treatment prognostic factors on imaging and pathology against survival outcomes | 3 years and 5 years | 
| To show mrTRG (Tumour Regression Grade) as a measurement tool can be reproduced by appropriately trained radiologists. | Agreement between local and centrally measured mrTRG (MRI Tumour Regression Grade) (mrTRG 1 good to mrTRG 5 poor) | Up to 2 years | 
| Surgical morbidity | Comparison by arm of early (30 day) surgical morbidity according to the Clavien-Dindo classification. | 30 days post operative | 
| Surgical morbidity | Comparison by arm of late (up to 12 months) surgical morbidity according to the Clavien-Dindo classification. | 12 months post operative | 
| To investigate the effect of the preoperative treatment regime on mrTRG measurement | Reporting of treatment given against measurement of mrTRG (MRI Tumour Regression Grade) response (mrTRG 1 good to mrTRG 5 poor) | Up to 2 years, 3 years and 5 years | 
| To investigate the effect of the preoperative treatment regime on survival outcomes | Reporting of treatment given survival outcomes | Up to 2 years, 3 years and 5 years | 
| To investigate the effect of mrTRG directed treatment strategy on Quality of Life | 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. | 1 year, 2 years, 3 years and 5 years | 
| To investigate the economic impact of introducing an mrTRG directed treatment strategy | Healthcare costs using NHS Reference Costs combined with health resource utilization and QoL data | Up to 2 years, 3 years and 5 years | 
| To define molecular and immunological characteristics associated with treatment response as measured by MRI (mrTRG). | 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 | Up to 2 years, 3 years and 5 years | 
| To assess whether the detection of ctDNA predicts for relapse in patients with locally advanced rectal cancer | Correlate ctDNA levels with outcome measures of mrTRG (MRI Tumour Regression Grade) (mrTRG 1 good to mrTRG 5 poor) and survival outcomes | Up to 2 years, 3 years and 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rectal Cancer, Magnetic Resonance Imaging, Chemoradiotherapy, Chemotherapy, Diagnostic Imaging