trigger rectal cancer trial protocol

mrTRG as a predictor for DFS

mrTRG vs DFSypT vs DFS

Royal Marsden database n=208 irradiated patients

Hypothesis

Treatment stratification according to an MRI response biomarker improve survival and

enhance quality of life after chemoradiotherapy in patients with rectal cancer.

Patient Benefits• First trial to stratify patients into ‘good’ and ‘poor’

chemoradiotherapy responders.

• Good responders - ? Avoid surgery, or less radical surgery

• Poor responders – improve survival

Trial DesignMulticentre blinded randomised control trial

mrTRG based stratification in intervention armInclusion:

• Adenocarcinoma 0-15cm from anal verge (radiologically)• Deemed to required CRT by recruiting trial centre

Exclusion:• Metastatic disease• MRI or Chemoradiotherapy contraindications• Previous pelvic malignancy, breast feeding or pregnant• Secondary concomitant malignancy

1) Biopsy - adenocarcinoma

2) Baseline MRI3) Chemoradiotherapy†

4) Eligible & Consent

Intervention arm

Repeat MRI and REASSESS (mrTRGa)

Control arm

mrTRG III-VmrTRG I&II

Good Response Poor Response

Repeat MRI*

Rectal Cancer

Clinical assessmentand baseline MRI

1:2 Randomisation‡

FOLFOX††

24 weeks

Adjuvant Therapy

FOLFOX††

24 weeks

Adjuvant Therapy

Deferral of surgery** Surgery

Repeat MRI (mrTRGb)

FOLFOX 12 weeks

Surgery

FOLFOX 12 weeks

†Recommended CRT regimen – 45Gy/25# and Capecitabine††Recommended post-treatment regime – FOLFOX regimen‡Randomise following MRI assessment but before the MRI is report at the MDT.*MRI to assesses disease progression only** TME surgery if patient declines deferral of surgery mrTRGa - performed at 6 weeks post-CRT mrTRGb - performed 12 weeks into ‘up-front’ FOLFOX treatment

TRIGGER Trial

EndpointsPrimary Endpoint – 1 year and 3 year QALY•Feasibility

recruit 100 patients, reflecting adequate safety, accurate radiology assessment (Kappa 0.7), patient and clinician equipoise

•Secondary Outcomes: Overall Survival, DFS Stoma free survival pTRG – can ‘upfront’ pre-operative chemotherapy improve pathological

evidence of response health economic evaluation – we anticipate the intervention arm will be

cheaper because it is possible to avoid surgery altogether in at least ¼ of these patients.

Quality of Life Adverse event reporting - CTCAE for surgical and therapeutic TUMOUR BIOLOGY – mrTRG1&2 v mrTRG3-5

1) Biopsy - adenocarcinoma

2) Baseline MRI3) Chemoradiotherapy†

4) Eligible & Consent

Intervention arm

Repeat MRI and REASSESS (mrTRGa)

Control arm

mrTRG III-VmrTRG I&II

Good Response Poor Response

Repeat MRI*

Rectal Cancer

Clinical assessmentand baseline MRI

1:2 Randomisation‡

FOLFOX††

24 weeks

Adjuvant Therapy

FOLFOX††

24 weeks

Adjuvant Therapy

Deferral of surgery** Surgery

Repeat MRI (mrTRGb)

FOLFOX 12 weeks

Surgery

FOLFOX 12 weeks

†Recommended CRT regimen – 45Gy/25# and Capecitabine††Recommended post-treatment regime – FOLFOX regimen‡Randomise following MRI assessment but before the MRI is report at the MDT.*MRI to assesses disease progression only** TME surgery if patient declines deferral of surgery mrTRGa - performed at 6 weeks post-CRT mrTRGb - performed 12 weeks into ‘up-front’ FOLFOX treatment

TRIGGER Trial