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Magnetic Resonance Tumor Regression Grade(mrTRG) as a Novel Biomarker to Stratify Management of Good and Poor Responders to Chemoradiotherapy: A Rectal Cancer Multicentre Randomised Control Trial -

SLCTR Registration Number

SLCTR/2017/012


Date of Registration

19 May 2017

The date of last modification

May 19, 2017



Application Summary


Scientific Title of Trial

Magnetic Resonance Tumor Regression Grade(mrTRG) as a Novel Biomarker to Stratify Management of Good and Poor Responders to Chemoradiotherapy: A Rectal Cancer Multicentre Randomised Control Trial


Public Title of Trial

Magnetic Resonance Tumour Regression Grade as Biomarker for Stratified Management of Rectal Cancer Patients


Disease of Health Condition(s) Studied

Rectal carcinoma


Scientific Acronym

TRIGGER


Public Acronym

None


Brief title

None


Universal Trial Number

None


Any other number(s) assigned to the trial and issuing authority

EudraCT 2015-003009-40; ClinicalTrials.gov Identifier: NCT02704520


Trial Details


What is the research question being addressed?

What is the accuracy of the novel imaging method magnetic resonance tumour regression grade (mrTRG) in assessing tumour response to chemoradiotherapy in patients with rectal cancer?


Type of study

Interventional


Study design

Allocation

Randomized controlled trial


Masking

Masking not used


Control

Active


Assignment

Parallel


Purpose

Treatment


Purpose

Phase 2-3


Intervention(s) planned

Study setting 1. University Surgical Unit of the Colombo South Teaching Hospital 2. National Cancer Institute, Maharagama

Method of Randomisation - simple randomisation with 2:1 ratio to intervention and control arms

Intervention
Patients in the intervention arm will be split into one of two groups according to their response to chemoradiotherapy. Patients who show a good response (mrTRG I&II) will be offered deferral of surgery and receive the standard 24-weeks of chemotherapy.

Patients who show a poor response (mrTRG III-V) will receive 12 weeks of chemotherapy (CAPOX [capecitabine and oxaliplatin] or FOLFOX [5-fluorouracil, oxaliplatin, folinic acid], or single agent capecitabine or 5-fluorouracil), undergo repeat restaging, and then continue to surgery or defer surgery, and receive the remaining 12 weeks of chemotherapy.

Control
Patients in the control arm will undergo surgery and then receive a 24-week course of chemotherapy (CAPOX [capecitabine and oxaliplatin] or FOLFOX [5-fluorouracil, oxaliplatin, folinic acid], or single agent capecitabine or 5-fluorouracil) and follow-up assessments as standard i.e. standard clinical practice. The doses will be titrated according to standard protocols.

All doses will be titrated according to standard protocols Both groups will be received other supportive care with no difference.


Inclusion criteria

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

Exclusion criteria

  1. Have metastatic disease (including resectable liver metastases).
  2. Are contraindicated for MRI e.g. non-MR compatible hip prosthesis, cardiac pacemaker.
  3. Are scheduled to receive less than 45Gy or more than 55Gy long course radiotherapy.
  4. Are contraindicated for chemoradiotherapy (CRT)
  5. 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.
  6. Are receiving or planned to receive treatment outside of that stipulated by the protocol, such as an alternative cytotoxic or investigational drug.
  7. Are pregnant, breastfeeding or unable / unwilling to comply with pregnancy prevention guidelines.
  8. 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


Primary outcome(s)

Patient recruitment rate Total number of patients randomised per month during the last 4 months from completion of recruitment


Primary outcome(s) - Time of assessment(s)

Last 4 months until completion of recruitment


Secondary outcome

  1. Pathology circumferential resection margin (pCRM) involvement rate Overall pCRM involvement rate between the control and intervention arm

  2. Drug toxicity [ Time Frame: Up to 1 year. ] Toxicity will be graded using Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Grade 3-5 adverse events will be compared between the control and intervention arms.

  3. Surgical morbidity [ Time Frame: 30 days and 12 months ] Surgical morbidity reported according to Clavien-Dindo classification

  4. Quality of surgery [ Time Frame: Time of surgery ] Quality of surgery determined using the mesorectal grading system.

  5. Strength of agreement of reported mrTRG between site and central radiologists [ Time Frame: At baseline and 5 years. ] Agreement (kappa) between site and central radiologists for reported mrTRG for MRI scans performed at baseline, post-CRT and during surveillance schedule.


Secondary outcome(s) - Time of assessment(s)

  1. pCRM involvement rate: Control arm: at 12 weeks. Intervention arm - poor response subgroup: 6 months. Intervention arm - good response subgroup: a median of 2 years.

  2. Drug toxicity: Up to 1 year.

  3. Surgical morbidity: At 30 days and 12 months

  4. Quality of surgery: At time of surgery

  5. Strength of agreement of reported mrTRG between site and central radiologists: At baseline and 5 years.



Target number/sample size

90 (60 in the intervention arm, 30 in the control arm) Expected enrollment from Sri Lanka: approx. 5 patients per month


Countries of recruitment

Sri Lanka, United Kingdom


Anticipated start date

2017-06-01


Anticipated end date

2021-12-01


Recruitment status

Pending


State of ethics review approval

Approved by Ethics approval has been granted by the Ethics Review Committee of the Faculty of Medical Sciences, University of Sri Jayewardenepura on 5th April 2017 (Ref: 11/17)


Funding source

Cancer research grant of the Faculty of Medical Sciences, University of Sri Jayawardenapura



Contact & Sponsor Information


Contact person for Scientific Queries/Principal Investigator

Dr. Bawantha Gamage
Senior Lecturer and Consultant Surgeon
Department of Surgery, Faculty of Medical Sciences University of Sri Jayawardenapura Sri Lanka

0718312897

bawanthagamage@gmail.com

Contact Person for Public Queries

Dr. Bawantha Gamage
Senior Lecturer and Consultant Surgeon
Department of Surgery, Faculty of Medical Sciences University of Sri Jayawardenapura

0718312897

bawanthagamage@gmail.com


Primary study sponsor/organization

Faculty of Medical Sciences

Faculty of Medical Sciences University of Sri Jayawardenapura Gangodawila, Nugegoda, sri Lannka
+94 11 2758539
+94 11 2801480
fms@sjp.ac.lk
http://medical.sjp.ac.lk/index.php

Secondary study sponsor (If any)

None