Neoadjuvant FOLFOXIRI and Chemoradiotherapy Versus Neoadjuvant CAPOX/FOLFOX and Chemoradiotherapy Followed by Surgery or a Watch-and-Wait Approach in High Risk Locally Advanced Rectal Cancer
MEND-IT II
MEND-IT II: Neoadjuvant FOLFOXIRI and Chemoradiotherapy Versus Neoadjuvant CAPOX/FOLFOX and Chemoradiotherapy, Followed by Surgery or a Watch-and-Wait Approach in High Risk Locally Advanced Rectal Cancer.
2 other identifiers
interventional
394
1 country
1
Brief Summary
The aim of this clinical trial is to compare triplet induction therapy (FOLFOXIRI) with doublet induction therapy (CAPOX/FOLFOX), followed by chemoradiotherapy and either surgery or a watch-and-wait approach, in patients with high-risk locally advanced rectal cancer. The primary questions it seeks to address are whether triplet induction therapy results in higher complete response rates, improved quality of life, and better long-term oncological outcomes compared to doublet induction therapy, despite the anticipated increased risk of toxicity.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P50-P75 for phase_3
Started Mar 2026
Longer than P75 for phase_3
1 active site
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
February 26, 2026
CompletedStudy Start
First participant enrolled
March 3, 2026
CompletedFirst Posted
Study publicly available on registry
March 16, 2026
CompletedPrimary Completion
Last participant's last visit for primary outcome
March 2, 2030
ExpectedStudy Completion
Last participant's last visit for all outcomes
March 2, 2034
March 16, 2026
March 1, 2026
4 years
February 26, 2026
March 10, 2026
Conditions
Keywords
Outcome Measures
Primary Outcomes (1)
Complete response
To evaluate if neoadjuvant FOLFOXIRI leads to higher pCR rates/sustained cCR rates (≥ 1 year) compared to neoadjuvant CAPOX/FOLFOX in patients with high risk LARC.
pCR: date of surgery sustained cCR: from date of surgery or date of entering a watch-and-wait approach, up until 1 year later.
Secondary Outcomes (19)
Regrowth free survival
3 and 5 years post-treatment.
Local recurrence free survival at 3 and 5 years
3 and 5 years post-treatment
Distant metastasis free survival
3 and 5 years post-treatment.
Progression free survival
3 and 5 years post-treatment.
Disease free survival (DFS)
3 and 5 years post-treatment
- +14 more secondary outcomes
Study Arms (3)
Triplet induction chemotherapy (FOLFOXIRI)
EXPERIMENTALTriplet induction chemotherapy (FOLFOXIRI) followed by chemoradiotherapy and surgery or a watch-and-wait approach.
Doublet induction chemotherapy (CAPOX/FOLFOX)
ACTIVE COMPARATORDoublet induction chemotherapy (FOLFOXIRI) followed by chemoradiotherapy and surgery or a watch-and-wait approach.
Registration arm: chemoradiotherapy alone
OTHERA registration arm in which patients who do not want to participate in the randomised study and who will receive chemoradiation alone as neoadjuvant treatment - followed by surgery or a Watch-and-Wait approach in accordance with standard-of-care.
Interventions
ICT consists of four or six two-weekly cycles of FOLFOXIRI. The dosages, dosage modification, and methods and schedule of administration of FOLFOXIRI follows the established treatment protocols and standard of care as prescribed in the Dutch Guidelines. It is administered as follows: * Day 1: irinotecan 165 mg/m2 body-surface area (BSA) intravenously (IV), followed by oxaliplatin 85mg/m2 BSA IV in combination with leucovorin 400mg/m2 BSA, followed by: * Day 1-2: 3200 mg/m2 BSA of continuous 5-fluorouracil IV * Day 3-14: rest days.
The dosages, dosage modification, and methods and schedule of administration of CAPOX follows the established treatment protocols and standard of care as prescribed in the Dutch Guidelines. CAPOX is administered as follows: * Day 1: Oxaliplatin 130 mg/m2 body-surface area \[BSA\], intravenously \[IV\]. * Day 1-14: Capecitabine 1000 mg/m2 BSA, orally, twice daily. * Day 15-21: Rest days. This regimen is initially administered for three cycles. In case of responsive or stable disease, a 4th cycle of CAPOX will be administered. In case of unacceptable toxicity (physician's discretion) to oxaliplatin, CAPOX may be continued as FOLFOX.
FOLFOX is a combination chemotherapy regimen, consisting of: * 5-fluorouracil (chemical name: L01BC02; trade name: 5-Fluorouracil; formulation: concentrate for solution for injection) * Oxaliplatin (chemical name: L01XA03; trade name: Oxaliplatin Accord; formulation: concentrate for solution for injection) FOLFOX is a well-established chemotherapy combination regimen for colorectal cancer, and is authorised for its intended use in this study. All FOLFOX component agents will be sourced from commercially available hospital stock and prepared according to standard protocols at participating centres.
In accordance with established standard-of-care protocols, chemoradiotherapy will commence 3-6 weeks after the completion of ICT, following restaging imaging and MDT review. The standard chemoradiotherapy regimen consists of external beam radiotherapy 50Gy in fractions of 2 Gy or 50.4 Gy in fractions of 1.8Gy combined with concomitant capecitabine, administered in accordance with Dutch Guidelines: * Dosage: 825 mg/m² Body Surface Area (BSA), twice daily * Route of administration: orally * Schedule: administered on all radiotherapy days * Treatment duration: 25 days In the case of cardiotoxicity or severe hand-foot syndrome due to capecitabine, treatment may be switched to Teysuno, in accordance with the Dutch guideline. The recommended dose of Teysuno in combination with oxaliplatin is 25 mg/m² body surface area, administered twice daily.
In patients with an incomplete response and resectable disease after first restaging, surgery is performed according to standard of care by a surgical oncologist with experience in rectal cancer surgery within 10-14 weeks after completion of chemoradiotherapy. The type and extent of the surgery is left to the discretion of the operating surgeon. In case of need for reconstructive surgery, the required specialist will be consulted and will attend the surgical procedure. The addition of IORT will be left to the discretion of the surgeon.
When a cCR is achieved after neoadjuvant therapy, patients may opt for a W\&W approach. A cCR is confirmed by imaging, endoscopy and digital rectal examination. Patients will receive a close surveillance follow up scheme according to the standard of care and local guidelines (51-54). Conduct follow-up every 3 months in the first year, every 6 months in the second year, and every 6 to 12 months in years 3 to 5, consisting of MRI and endoscopic evaluation. If any changes to the scar are detected during follow-up, a biopsy should be performed.
Eligibility Criteria
You may qualify if:
- years or older
- WHO performance score 0-1.
- Fit for (modified dose) triple chemotherapy (FOLFOXIRI)
- Histopathological confirmed rectal cancer. (Lower border of the tumour located on or below the sigmoidal take-off as established on MRI of the pelvis.)
- Confirmed high-risk locally advanced rectal cancer, at high risk of treatment failure, meeting one of the following imaging-based criteria:
- cT4b-tumour or evident tumour invasion of the MRF: distance to MRF 0 mm AND thickening of the MRF over a length of approximately 5 mm (MRF ≤ 1 mm is not considered sufficient).
- The presence of grade 4 extramural venous invasion (mrEMVI)
- The presence of tumour deposits (TD)
- The presence of bilateral extramesorectal lymph nodes with a short-axis size ≥ 7mm (LLN) or extensive LLN involving pelvic side wall structures, at high risk of an incomplete resection.
- Resectable disease as determined on magnetic resonance imaging (MRI) or deemed resectable disease after neoadjuvant treatment. (Expected gross incomplete resection with overt tumour remaining in the patient after resection, tumour invasion in the neuroforamina, encasement of the ischiatic nerve and invasion of the cortex from S2 and upwards are considered not resectable.)
- Written informed consent.
You may not qualify if:
- Homozygous DPD deficiency.
- Any chemotherapy within the past 6 months.
- Any contraindication for the planned systemic therapy (e.g., severe allergy, pregnancy, kidney dysfunction and thrombocytopenia), as determined by the medical oncologist.
- Previous radiotherapy in the pelvic area precluding chemoradiotherapy with a dose of 50 - 50.4 Gy.
- Any contraindication for the planned chemoradiotherapy (e.g., severe allergy to the chemotherapy agent or no possibility to receive radiotherapy), as determined by the medical oncologist and/or radiation oncologist.
- Any contraindication to undergo surgery, as determined by the surgeon and/or anaesthesiologist.
- Concurrent malignancies that interfere with the planned study treatment or the prognosis of the resected tumour.
- Microsatellite instability (MSI).
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (1)
Catharina Hospital Eindhoven
Eindhoven, North Brabant, 5623 EJ, Netherlands
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Study Officials
- PRINCIPAL INVESTIGATOR
Jacobus WA Burger, Prof. dr.
Catharina Ziekenhuis Eindhoven
Central Study Contacts
Study Design
- Study Type
- interventional
- Phase
- phase 3
- Allocation
- RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- OTHER
- Responsible Party
- SPONSOR INVESTIGATOR
- PI Title
- Prof. dr.
Study Record Dates
First Submitted
February 26, 2026
First Posted
March 16, 2026
Study Start
March 3, 2026
Primary Completion (Estimated)
March 2, 2030
Study Completion (Estimated)
March 2, 2034
Last Updated
March 16, 2026
Record last verified: 2026-03