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

Rectal Cancer Clinical Trial

— TRIGGER  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02704520
• Other study ID #: DOCUMAS: 23HH8209
• Status: Recruiting
• Phase: N/A
• Start date: March 2016
• Est. completion date: December 2034

Study information

• Verified date: September 2023
• Source: Imperial College London
• Contact: Caroline Martin
• Phone: +44 (0) 7749 655 817
• Email: cmartin1[@]imperial.ac.uk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 441
• Est. completion date: December 2034
• Est. primary completion date: December 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 16 Years and older

Eligibility

Inclusion Criteria:

1. MRI defined locally advanced rectal carcinoma i.e. one or more: greater than or equal to mrT3c; mrEMVI positive; mr N1c; mr CRM positive

2. Biopsy confirmed adenocarcinoma of radiologically defined rectum

3. Be deemed to require preoperative chemoradiotherapy (CRT) or total neoadjuvant therapy (TNT)

Exclusion Criteria:

1. Metastatic disease

2. MRI, radiotherapy and/or chemotherapy contraindications

3. A post-treatment MRI performed more than 10 weeks after the completion of radiotherapy if given

4. Previous malignancy within preceding 5 years if risk of recurrence >5%

Related Conditions & MeSH terms

• Rectal Cancer
• Rectal Neoplasms

Intervention

Diagnostic Test:
• High resolution MRI scan
MRI reporting of tumour but not mrTRG in the control arm = standard of care
• mrTRG assessment
Watch and wait offered for good responders Consider further treatment for poor responders

Locations

Country	Name	City	State
United Kingdom	Aberdeen Royal Infirmary - NHS Grampion	Aberdeen	Aberdeenshire
United Kingdom	Hampshire Hospitals NHS Foundation Trust	Basingstoke	Hampshire
United Kingdom	Bristol Royal Infirmary	Bristol
United Kingdom	Colchester General Hospital	Colchester
United Kingdom	NHS Lanarkshire - Hairmyres Hospital	East Kilbride
United Kingdom	Diana Princess of Wales Hospital	Grimsby
United Kingdom	Salisbury NHS Foundation Trust	Salisbury	Wiltshire
United Kingdom	University Hospital of North Tees	Stockton-on-Tees
United Kingdom	University Hospital of North Midlands NHS Trust - Royal Stoke	Stoke-on-Trent	Staffordshire
United Kingdom	Royal Marsden NHS Foundation Trust	Sutton

Sponsors (1)

Lead Sponsor	Collaborator
Imperial College London

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	Surgical morbidity	Comparison by arm of early (30 day) surgical morbidity according to the Clavien-Dindo classification.	30 days post operative
Secondary	Surgical morbidity	Comparison by arm of late (up to 12 months) surgical morbidity according to the Clavien-Dindo classification.	12 months post operative
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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