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

Primary Purpose

Rectal Cancer

Status

Recruiting

Phase

Not Applicable

Locations

United Kingdom

Study Type

Interventional

Intervention

High resolution MRI scan

mrTRG assessment

About this trial

This is an interventional treatment trial for Rectal Cancer focused on measuring Rectal Cancer, Magnetic Resonance Imaging, Chemoradiotherapy, Chemotherapy, Diagnostic Imaging

Eligibility Criteria

16 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Have a biopsy-confirmed adenocarcinoma 0-15cm from the anal verge (on MRI or rigid sigmoidoscopy).
Have locally Advanced Rectal Carcinoma diagnosed by MRI (mrCRM unsafe or ≥mrT3c [>5mm beyond muscularis propria] or mrEMVI positive disease)
Be deemed to require chemoradiotherapy.
Scheduled to receive 45Gy - 55Gy long course radiotherapy.
Have provided written informed consent to participate in the study.
Be aged 18 years or over.

Exclusion Criteria:

Have metastatic disease (including resectable liver metastases).
Are contraindicated for MRI e.g. non-MR compatible hip prosthesis, cardiac pacemaker.
Are scheduled to receive less than 45Gy or more than 55Gy long course radiotherapy.
Are contraindicated for chemoradiotherapy (CRT)
Hypersensitivity or contraindication to the drug(s) associated with the planned choice of systemic chemotherapy (CAPOX, FOLFOX or single agent 5-FU or capecitabine) as stated in the SmPC for each of the drugs.
Are receiving or planned to receive treatment outside of that stipulated by the protocol, such as an alternative cytotoxic or investigational drug.
Are pregnant, breastfeeding or unable / unwilling to comply with pregnancy prevention guidelines.
Any other malignant disease within the preceding 5 years with the exception of non- melanomatous skin cancer, carcinoma in situ and early stage disease with <5% recurrence risk.

Sites / Locations

Aberdeen Royal Infirmary - NHS GrampionRecruiting
Hampshire Hospitals NHS Foundation TrustRecruiting
University Hospital of North Midlands NHS Trust - Royal StokeRecruiting
Salisbury NHS Foundation TrustRecruiting
Bristol Royal InfirmaryRecruiting
Colchester General HospitalRecruiting
NHS Lanarkshire - Hairmyres HospitalRecruiting
Diana Princess of Wales HospitalRecruiting
University Hospital of North TeesRecruiting
Royal Marsden NHS Foundation TrustRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Other

Experimental

Arm Label

Control arm

Intervention arm

Arm Description

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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

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)

Surgical morbidity

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

Surgical morbidity

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

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)

To investigate the effect of the preoperative treatment regime on survival outcomes

Reporting of treatment given survival outcomes

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.

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

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

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

Full Information

NCT ID

NCT02704520

First Posted

February 5, 2016

Last Updated

September 1, 2023

Sponsor

Imperial College London

1. Study Identification

Unique Protocol Identification Number

NCT02704520

Brief Title

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

Acronym

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

Study Type

Interventional

2. Study Status

Record Verification Date

September 2023

Overall Recruitment Status

Recruiting

Study Start Date

March 2016 (undefined)

Primary Completion Date

December 2027 (Anticipated)

Study Completion Date

December 2034 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Imperial College London

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief 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.

Detailed 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Rectal Cancer

Keywords

Rectal Cancer, Magnetic Resonance Imaging, Chemoradiotherapy, Chemotherapy, Diagnostic Imaging

7. Study Design

Primary Purpose

Treatment

Study Phase

Not Applicable

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

441 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Control arm

Arm Type

Other

Arm Description

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

Arm Title

Intervention arm

Arm Type

Experimental

Arm Description

Intervention Type

Diagnostic Test

Intervention Name(s)

High resolution MRI scan

Intervention Description

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

Intervention Type

Diagnostic Test

Intervention Name(s)

mrTRG assessment

Intervention Description

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

Primary Outcome Measure Information:

Title

To show that patients can successfully avoid surgery after achieving a good response to treatment as measured on MRI (mrTRG).

Description

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.

Time Frame

Up to 5 years

Secondary Outcome Measure Information:

Title

To describe the prognostic features associated with good and poor response to treatment as measured by MRI (mrTRG)

Description

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

Time Frame

3 years and 5 years

Title

To show mrTRG (Tumour Regression Grade) as a measurement tool can be reproduced by appropriately trained radiologists.

Description

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

Time Frame

Up to 2 years

Title

Surgical morbidity

Description

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

Time Frame

30 days post operative

Title

Surgical morbidity

Description

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

Time Frame

12 months post operative

Title

To investigate the effect of the preoperative treatment regime on mrTRG measurement

Description

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

Time Frame

Up to 2 years, 3 years and 5 years

Title

To investigate the effect of the preoperative treatment regime on survival outcomes

Description

Reporting of treatment given survival outcomes

Time Frame

Up to 2 years, 3 years and 5 years

Title

To investigate the effect of mrTRG directed treatment strategy on Quality of Life

Description

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.

Time Frame

1 year, 2 years, 3 years and 5 years

Title

To investigate the economic impact of introducing an mrTRG directed treatment strategy

Description

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

Time Frame

Up to 2 years, 3 years and 5 years

Title

To define molecular and immunological characteristics associated with treatment response as measured by MRI (mrTRG).

Description

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

Time Frame

Up to 2 years, 3 years and 5 years

Title

To assess whether the detection of ctDNA predicts for relapse in patients with locally advanced rectal cancer

Description

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

Time Frame

Up to 2 years, 3 years and 5 years

10. Eligibility

Sex

All

Minimum Age & Unit of Time

16 Years

Accepts Healthy Volunteers

Eligibility Criteria

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%

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Caroline Martin

Phone

+44 (0) 7749 655 817

cmartin1@imperial.ac.uk

First Name & Middle Initial & Last Name or Official Title & Degree

Syvella Ellis

Phone

+44 (0) 7732 315 234

giclinicaltrials@imperial.ac.uk

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Gina Brown, MD

Organizational Affiliation

Imperial College London

Official's Role

Principal Investigator

Facility Information:

Facility Name

Aberdeen Royal Infirmary - NHS Grampion

City

Aberdeen

State/Province

Aberdeenshire

ZIP/Postal Code

AB252ZN

Country

United Kingdom

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Angela Cheyne

Phone

01224 554870

angela.cheyne@nhs.net

First Name & Middle Initial & Last Name & Degree

Sue Rodwell

Phone

01224 553830

s.rodwell@nhs.net

Facility Name

Hampshire Hospitals NHS Foundation Trust

City

Basingstoke

State/Province

Hampshire

ZIP/Postal Code

RG24 9NA

Country

United Kingdom

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Megan Topping

Phone

01256 313918

megan.topping@hhft.nhs.uk

First Name & Middle Initial & Last Name & Degree

Caroline Palmer

Phone

01256 313918

caroline.palmer@hhft.nhs.uk

First Name & Middle Initial & Last Name & Degree

Brendan Moran, MD

First Name & Middle Initial & Last Name & Degree

Mit Dattani, MD

Facility Name

University Hospital of North Midlands NHS Trust - Royal Stoke

City

Stoke-on-Trent

State/Province

Staffordshire

ZIP/Postal Code

ST4 6QS

Country

United Kingdom

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Katrina Parkinson

Phone

01782 672621

katrina.parkinson@uhnm.nhs.uk

First Name & Middle Initial & Last Name & Degree

Angela Peake

Phone

01782 672258

angela.peake@uhnm.nhs.uk

Facility Name

Salisbury NHS Foundation Trust

City

Salisbury

State/Province

Wiltshire

ZIP/Postal Code

SP2 8BJ

Country

United Kingdom

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Sophia Strong-Sheldrake

Phone

01722 336262

Ext

4191

sophia.strong-sheldrake@salisbury.nhs.uk

First Name & Middle Initial & Last Name & Degree

Julie Attlee

Phone

01722 336262

Ext

4191

julie.attlee@salisbury.nhs.uk

First Name & Middle Initial & Last Name & Degree

Graham Branagan, MD

First Name & Middle Initial & Last Name & Degree

Alaaeldin Shablak, MD

Facility Name

Bristol Royal Infirmary

City

Bristol

ZIP/Postal Code

BS2 8ED

Country

United Kingdom

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Robert Hollister

Phone

+44 1173426742

robert.hollister@uhbristol.nhs.uk

First Name & Middle Initial & Last Name & Degree

Stephen Falk, MD

Facility Name

Colchester General Hospital

City

Colchester

ZIP/Postal Code

CO4 5JL

Country

United Kingdom

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Lucy Thorogood

Phone

+44 1206 745 355

lucy.thorogood@colchesterhospital.nhs.uk

First Name & Middle Initial & Last Name & Degree

Celine Driscoll

Phone

+44 1206 745 355

celine.driscoll@colchesterhospital.nhs.uk

First Name & Middle Initial & Last Name & Degree

Bruce Sizer, MD

Facility Name

NHS Lanarkshire - Hairmyres Hospital

City

East Kilbride

ZIP/Postal Code

G75 8RG

Country

United Kingdom

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Louise Devlin

Phone

+44 1355 585329

louise.devlin@lanarkshire.scot.nhs.uk

First Name & Middle Initial & Last Name & Degree

Angela Scullion

Phone

+44 1355 585 329

angela.scullion@lanarkshire.scot.nhs.uk

First Name & Middle Initial & Last Name & Degree

Cindy Chew, MD

Facility Name

Diana Princess of Wales Hospital

City

Grimsby

ZIP/Postal Code

DN33 2BA

Country

United Kingdom

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Jonathan Hatton

Phone

+44 3033 303555

jonathan.hatton@nhs.net

First Name & Middle Initial & Last Name & Degree

Rajarshi Roy, MD

Facility Name

University Hospital of North Tees

City

Stockton-on-Tees

ZIP/Postal Code

TS19 8PE

Country

United Kingdom

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Helen Wilson

Phone

+44 1642 383 277

Helen.Wilson2@nth.nhs.uk

First Name & Middle Initial & Last Name & Degree

Lynda Poole

Phone

+44 1642 383 277

Lynda.Poole@nth.nhs.uk

First Name & Middle Initial & Last Name & Degree

David Wilson, MD

Facility Name

Royal Marsden NHS Foundation Trust

City

Sutton

ZIP/Postal Code

SM2 5PT

Country

United Kingdom

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Cordelia Grant

cordelia.grant@rmh.nhs.uk

First Name & Middle Initial & Last Name & Degree

Sheela Rao, MD

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

28851403

Citation

Battersby NJ, Dattani M, Rao S, Cunningham D, Tait D, Adams R, Moran BJ, Khakoo S, Tekkis P, Rasheed S, Mirnezami A, Quirke P, West NP, Nagtegaal I, Chong I, Sadanandam A, Valeri N, Thomas K, Frost M, Brown G. A rectal cancer feasibility study with an embedded phase III trial design assessing magnetic resonance tumour regression grade (mrTRG) as a novel biomarker to stratify management by good and poor response to chemoradiotherapy (TRIGGER): study protocol for a randomised controlled trial. Trials. 2017 Aug 29;18(1):394. doi: 10.1186/s13063-017-2085-2.

Results Reference

derived

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

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