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Trial registered on ANZCTR


Registration number
ACTRN12625000583448
Ethics application status
Approved
Date submitted
30/04/2025
Date registered
4/06/2025
Date last updated
4/06/2025
Date data sharing statement initially provided
4/06/2025
Type of registration
Prospectively registered

Titles & IDs
Public title
Total Neoadjuvant Therapy for Organ Preservation in Early-Stage Low Rectal Cancer
Scientific title
Total Neoadjuvant Therapy for Organ Preservation in Early-Stage Low Rectal Cancer: The EARLY-TNT Trial
Secondary ID [1] 314332 0
None
Universal Trial Number (UTN)
Trial acronym
EARLY-TNT Trial
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Rectal Cancer 337297 0
Condition category
Condition code
Cancer 333688 333688 0 0
Bowel - Back passage (rectum) or large bowel (colon)

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This trial is an investigator-initiated, multicentre, single-arm phase II study. In this study, patients with early-stage (cT2-3, N0, M0) low rectal cancer will receive Total Neoadjuvant Therapy (TNT).

The preferred regime for consolidation TNT comprises the following:
• Long course chemoradiotherapy (6 weeks)
o 50 Gy external beam modulated radiation in 25 fractions over 5 weeks
o 5-FU infusion via pump for the period, or capecitabine orally 5 days per week
• Wait 2-4 weeks after completion of radiotherapy
• Consolidation chemotherapy (total 16-18 weeks)
o 4 cycles mFOLFOX6/ FOLFOX, 2nd weekly for 8 weeks OR 3 cycles CAPOX for 9 weeks
o Then complete first response assessment (comprises rectal exam, flexible sigmoidoscopy and MRI pelvis)
o Depending on outcome of above, give remaining 4 cycles of mFOLFOX6 (or FOLFOX) OR 3 cycles of CAPOX
• Wait 2-4 weeks and perform second response assessment (comprises rectal exam, flexible sigmoidoscopy and MRI pelvis)

Chemotherapy agents
• mFOLFOX6/FOLFOX
o Oxaliplatin, 85 mg/m2 intravenous (IV) infusion on day 1 of cycle
o Calcium Folinate (Leucovorin) 50 mg IV bolus on day 1 of cycle
o Fluorouracil 400 mg/m2 IV and 2400 mg/m2 IV infusion via pump over 46 hours on day 1 of cycle
• CAPOX
o Oxaliplatin 130 mg/m2 IV infusion on day 1 of cycle
o Capecitabine 1000 mg/m2 twice a day orally for 2 weeks

Variations of neoadjuvant therapy and dose adaptations
To maximise opportunity for enrolment and best reflect the heterogeneity of real-world clinical practice, variations in TNT protocols at the discretion of the treating team will be allowed for within the following constraints:
• If FOLFOX is utilised, intended course must comprise no less than 4 cycles, up to 8 cycles
• If CAPOX is utilised, intended course must comprise no less than 3 cycles, up to 6 cycles
Dose adaptations (i.e. dose reduction in event of poor tolerance or toxicity) or early cessation of neoadjuvant therapy is left at the discretion of the treating team.

Adherence will be assessed through attendance at outpatient oncology sessions and review of medical records.
Intervention code [1] 330946 0
Treatment: Drugs
Intervention code [2] 331052 0
Treatment: Other
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 341281 0
Proportion of patients with complete clinical response (cCR)
Assessment method [1] 341281 0
Response Assessment (rectal exam, flexible sigmoidoscopy, MRI pelvis) with referenced to criteria for cCR Criteria for cCR are: Rectal exam: no palpable tumour Flexible sigmoidoscopy: • No visible tumour AND white scar • Negative biopsies not mandatory MRI pelvis: TRG 1 or 2 • Substantial downsizing with no residual tumour • OR residual fibrosis only • OR residual wall thickening due to oedema with fibrosis • AND no suspicious lymph nodes / EMVI
Timepoint [1] 341281 0
At first (halfway point of consolidation chemotherapy) +/- second (at conclusion of consolidation chemotherapy) response assessments
Secondary outcome [1] 447009 0
Proportion of patients with near clinical response (nCR) or incomplete clinical response (iCR)
Assessment method [1] 447009 0
Response Assessment (rectal exam, flexible sigmoidoscopy, MRI pelvis) with reference to criteria for nCR/iCR Criteria for nCR: Rectal exam: minor palpable irregularity Flexible sigmoidoscopy: • Residual flat ulcer • Negative biopsy mandatory MRI pelvis: TRG 1 or 2 • Substantial downsizing with no residual tumour • OR residual fibrosis only • OR residual wall thickening due to oedema with fibrosis • AND no suspicious lymph nodes / EMVI An incomplete clinical response (iCR) refers to any response less than nCR that is not progressive disease.
Timepoint [1] 447009 0
First +/- second response assessments, and surveillance encounters (3-6 monthly for up to 5 years)
Secondary outcome [2] 447010 0
Organ preservation rate (TME-free survival)
Assessment method [2] 447010 0
Review of medical records
Timepoint [2] 447010 0
3 and 5 year follow up (post commencement of treatment)
Secondary outcome [3] 447011 0
R0 resection rate amongst patients who undergo surgery
Assessment method [3] 447011 0
Review of medical records
Timepoint [3] 447011 0
Following undergoing surgery (if applicable) - assessed at time of release of histology report
Secondary outcome [4] 447012 0
Local recurrence rates and location
Assessment method [4] 447012 0
Review of medical records
Timepoint [4] 447012 0
At each surveillance encounter (3-6 monthly, for up to 5 years)
Secondary outcome [5] 447013 0
Adverse events
Assessment method [5] 447013 0
Review of medical records. For surgery, reported descriptively and using Clavien-Dindo grade
Timepoint [5] 447013 0
Daily in-hospital and 30 days post discharge from hospital
Secondary outcome [6] 447014 0
Patient reported outcomes - burden of colorectal cancer
Assessment method [6] 447014 0
Using 'Assessment of Burden of ColoRectal Cancer (ABCRC)' tool
Timepoint [6] 447014 0
At study registration, re-staging following TNT and then at 24 months and 36 months post registration
Secondary outcome [7] 447522 0
Treatment toxicity
Assessment method [7] 447522 0
Review of medical records. Reported descriptively and using Common Terminology Criteria for Adverse Events (CTCAE) version 6
Timepoint [7] 447522 0
In hospital (daily) and 30 days (post discharge)
Secondary outcome [8] 447523 0
Patient reported outcomes - Low Anterior Resection Syndrome
Assessment method [8] 447523 0
Using 'Low Anterior Resection Syndrome (LARS)' score
Timepoint [8] 447523 0
At study registration, re-staging following TNT and then at 24 months and 36 months post registration
Secondary outcome [9] 447524 0
Patient reported outcomes - treatment related adverse events
Assessment method [9] 447524 0
Using 'Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE)'
Timepoint [9] 447524 0
At study registration, re-staging following TNT and then at 24 months and 36 months post registration
Secondary outcome [10] 447525 0
Disease-free survival
Assessment method [10] 447525 0
Review of medical records
Timepoint [10] 447525 0
3 and 5 year follow up following commencement of treatment
Secondary outcome [11] 447526 0
Overall survival
Assessment method [11] 447526 0
Review of medical records
Timepoint [11] 447526 0
3 and 5 year follow up following commencement of treatment
Secondary outcome [12] 447527 0
Complete pathological response rate
Assessment method [12] 447527 0
Review of medical records
Timepoint [12] 447527 0
Following undergoing surgery (if applicable) - assessed at time of release of histology report
Secondary outcome [13] 447528 0
Response grade in patients who undergo surgery
Assessment method [13] 447528 0
Review of medical records
Timepoint [13] 447528 0
Following undergoing surgery (if applicable) - assessed at time of release of histology report
Secondary outcome [14] 447529 0
Distant recurrence rates and location
Assessment method [14] 447529 0
Review of medical records
Timepoint [14] 447529 0
At each surveillance encounter (3-6 monthly, for up to 5 years)

Eligibility
Key inclusion criteria
Inclusion criteria (patients must meet all the following criteria):
• Age 18-85 years.
• Histologically confirmed rectal adenocarcinoma.
• Lowest part of tumour within 10 cm of anal verge on MRI or sigmoidoscopy.
• cT2-T3, N0, M0 rectal cancer based on clinical staging.
• No extramural vascular invasion (EMVI) or threatened Mesorectal fascia (MRF) on MRI.
Minimum age
18 Years
Maximum age
85 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Unable to undergo MRI staging
• Malignant polyp / T1 cancer
• Deficient mismatch repair (dMMR) / microsatellite instability high (MSI-H) cancer
• Recurrent rectal cancer
• Prior pelvic radiotherapy
• Prior chemotherapy or surgery for rectal cancer (including diverting colostomy or transanal excision) prior to the initiation of neoadjuvant therapy
• Women who are pregnant / within 28 days post-partum / breast feeding / wishing to preserve ovarian function / fertility
• Active infections requiring systemic antibiotic treatment
• Other active malignancy (with exception of adequately treated basal cell / squamous cell skin cancer or in situ cervical cancer)
• Inability to provide informed consent

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 2
Type of endpoint/s
Efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
5/06/2025
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
30
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA

Funding & Sponsors
Funding source category [1] 318851 0
Self funded/Unfunded
Name [1] 318851 0
Country [1] 318851 0
Primary sponsor type
Hospital
Name
Royal Adelaide Hospital / Central Adelaide Local Health Network
Country
Australia
Secondary sponsor category [1] 321306 0
None
Name [1] 321306 0
Country [1] 321306 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 317467 0
Central Adelaide Local Health Network HREC
Ethics committee address [1] 317467 0
Ethics committee country [1] 317467 0
Australia
Date submitted for ethics approval [1] 317467 0
17/04/2025
Approval date [1] 317467 0
23/04/2025
Ethics approval number [1] 317467 0

Summary
Brief summary
Trial website
Public notes

Contacts
Principal investigator
Name 141134 0
A/Prof Tarik Sammour
Address 141134 0
Colorectal Unit, Royal Adelaide Hospital, Port Road, Adelaide SOUTH AUSTRALIA, 5000
Country 141134 0
Australia
Phone 141134 0
+61 870742164
Email 141134 0
tarik.sammour@sa.gov.au
Contact person for public queries
Name 141135 0
Zachary Bunjo
Address 141135 0
Colorectal Unit, Royal Adelaide Hospital, Port Road, Adelaide SOUTH AUSTRALIA, 5000
Country 141135 0
Australia
Phone 141135 0
+61 870742164
Email 141135 0
zachary.bunjo@sa.gov.au
Contact person for scientific queries
Name 141136 0
Zachary Bunjo
Address 141136 0
Colorectal Unit, Royal Adelaide Hospital, Port Road, Adelaide SOUTH AUSTRALIA, 5000
Country 141136 0
Australia
Phone 141136 0
+61 870742164
Email 141136 0
zachary.bunjo@sa.gov.au

Data sharing statement
Will the study consider sharing individual participant data?
No


What supporting documents are/will be available?

No Supporting Document Provided


Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.