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

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

Overview

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.

Interventions

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

Primary outcome measures

• To show that patients can successfully avoid surgery after achieving a good response to treatment as measured on MRI (mrTRG). [Time frame: Up to 5 years]

Secondary outcome measures (10)

• To describe the prognostic features associated with good and poor response to treatment as measured by MRI (mrTRG) [Time frame: 3 years and 5 years]
• To show mrTRG (Tumour Regression Grade) as a measurement tool can be reproduced by appropriately trained radiologists. [Time frame: Up to 2 years]
• Surgical morbidity [Time frame: 30 days post operative]
• Surgical morbidity [Time frame: 12 months post operative]
• To investigate the effect of the preoperative treatment regime on mrTRG measurement [Time frame: Up to 2 years, 3 years and 5 years]
• To investigate the effect of the preoperative treatment regime on survival outcomes [Time frame: Up to 2 years, 3 years and 5 years]
• To investigate the effect of mrTRG directed treatment strategy on Quality of Life [Time frame: 1 year, 2 years, 3 years and 5 years]
• To investigate the economic impact of introducing an mrTRG directed treatment strategy [Time frame: Up to 2 years, 3 years and 5 years]
• To define molecular and immunological characteristics associated with treatment response as measured by MRI (mrTRG). [Time frame: 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 [Time frame: Up to 2 years, 3 years and 5 years]

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%

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

United Kingdom · 10 centers

• Aberdeen Royal Infirmary - NHS Grampion — Aberdeen
• Hampshire Hospitals NHS Foundation Trust — Basingstoke
• University Hospital of North Midlands NHS Trust - Royal Stoke — Stoke-on-Trent
• Salisbury NHS Foundation Trust — Salisbury
• Bristol Royal Infirmary — Bristol
• Colchester General Hospital — Colchester
• NHS Lanarkshire - Hairmyres Hospital — East Kilbride
• Diana Princess of Wales Hospital — Grimsby
• … and 2 more centers

Publications

• 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 PMID 28851403

Identifiers

NCT: NCT02704520 · DOCUMAS: 23HH8209

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗