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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Catharina Ziekenhuis Stichting

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

11 Mar 2026 → ongoing

Decision date (initial)

2026-02-04

Transition trial

No

Low-intervention

Yes

Rare-disease indication

No

Vulnerable population

No

Funding sources

MedZO

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy

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 locally advanced rectal cancer

Secondary objectives 11

1. To compare long term oncological outcomes at 3- and 5 years between neoadjuvant FOLFOXIRI and neoadjuvant CAPOX/FOLFOX.
2. To compare radiological response between neoadjuvant FOLFOXIRI and neoadjuvant CAPOX/FOLFOX.
3. To compare pathological response between neoadjuvant FOLFOXIRI and neoadjuvant CAPOX/FOLFOX.
4. To compare toxicity related to induction chemotherapy between neoadjuvant FOLFOXIRI and neoadjuvant CAPOX/FOLFOX.
5. To compare the completion rates of induction chemotherapy and chemoradiotherapy, both separately and combined, between neoadjuvant FOLFOXIRI and neoadjuvant CAPOX/FOLFOX.
6. To compare the number of patients undergoing surgery between neoadjuvant FOLFOXIRI and neoadjuvant CAPOX/FOLFOX.
7. To compare surgical characteristics between neoadjuvant FOLFOXIRI and neoadjuvant CAPOX/FOLFOX.
8. To compare post-operative morbidity between neoadjuvant FOLFOXIRI and neoadjuvant CAPOX/FOLFOX.
9. To compare quality of life between neoadjuvant FOLFOXIRI and neoadjuvant CAPOX/FOLFOX.
10. To compare work productivity and activity impairment between neoadjuvant FOLFOXIRI and neoadjuvant CAPOX/FOLFOX.
11. To compare cost-effectiveness and -utility between neoadjuvant FOLFOXIRI and neoadjuvant CAPOX/FOLFOX.

Conditions and MedDRA coding

locally advanced rectal cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. 18 years or older
2. WHO performance score 0-1
3. Fit for (modified dose) triple chemotherapy (FOLFOXIRI)
4. Histopathological confirmed rectal cancer
5. Confirmed high-risk locally advanced rectal cancer, at high risk of treatment failure, meeting one of the following imaging-based criteria: cT4b or evident tumour invasion of the MRF, EMVI grade IV, tumour deposits, bilateral or extensive unilateral extramesorectal lymph nodes ≥ 7mm
6. Resectable disease as determined on magnetic resonance imaging (MRI) or deemed resectable disease after neoadjuvant treatment
7. 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
8. Written informed consent

Exclusion criteria 9

1. Evidence of metastatic disease at time of inclusion or within six months prior to inclusion except for patients with enlarged iliac or inguinal lymph nodes and non-specific lung noduli
2. Homozygous DPD deficiency
3. Any chemotherapy within the past 6 months
4. Any contraindication for the planned systemic therapy (e.g., severe allergy, pregnancy, kidney dysfunction and thrombocytopenia), as determined by the medical oncologist
5. Previous radiotherapy in the pelvic area precluding chemoradiotherapy with a dose of 50 – 50.4 Gy
6. 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
7. Any contraindication to undergo surgery, as determined by the surgeon and/or anaesthesiologist
8. Concurrent malignancies that interfere with the planned study treatment or the prognosis of the resected tumour
9. Microsatellite instability (MSI)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. pCR post operatively: The pathological response is evaluated by an experienced pathologist in one of the participating centres and noted in the patient’s medical file. A pathological complete response is defined as the absence of residual tumour cells in the complete resected specimen including all resected regional lymph nodes (ypT0N0) according to the 8th edition of the UICC TNM classification of malignant tumours.
2. cCR at 1 year: The clinical response is evaluated by an experienced radiologist in one of the participating centres and noted in the patients’ medical file. A cCR is defined as the absence of viable tumour tissue based on magnetic resonance imaging and endoscopic evaluation. In case of a sustained cCR at 1 year, there is no regrowth or viable tumour tissue present on magnetic resonance imaging and endoscopy 1 year after the last day of chemoradiotherapy.

Secondary endpoints 23

1. Regrowth free survival at 3 and 5 years. Regrowth is defined as endoluminal or locoregional nodal recurrence after cCR in a watch and wait approach.
2. Local recurrence free survival at 3 and 5 years. Local recurrence is defined as locoregional recurrence after TME-surgery. Local recurrence is confirmed by either radiological or histopathological examination.
3. Distant metastasis free survival at 3 and 5 years. Distant metastasis is confirmed by either radiological or histopathological examination.
4. Progression free survival at 3 and 5 years. Progression is defined as progression of the primary tumour, local recurrence or distant metastases, confirmed by radiological or histopathological examination or death.
5. Disease free survival (DFS) at 3 and 5 years. DFS is defined as no confirmed signs of local recurrence, distant metastases or death.
6. Overall survival at 3 and 5 years.
7. Successful organ preservation at 1 and 3 years. Organ preservation is considered to have failed if the rectum is removed; if the patient develops an unequivocal locoregional cancer recurrence or if the patient has a stoma.
8. Radiological response after induction chemotherapy. Assessment and reporting of all MRI scans is performed by the radiologist according to a standard operating procedure and is registered in the patient’s medical file.
9. Radiological response after chemoradiotherapy. Assessment and reporting of all MRI scans is performed by the radiologist according to a standard operating procedure and is registered in the patient’s medical file.
10. Pathological response as determined by Mandard grading system. The Mandard score is registered by the pathologist in the patient's medical file.
11. Toxicity related to induction chemotherapy, graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Toxicity related to induction chemotherapy will be scored from day one of the first cycle until one month after the last administration of induction chemotherapy and is registered in the patient’s medical file by the treating oncologist. All CTCAE grade ≥ 2 and haematological CTCAE ≥ 3 AEs are registered.
12. Compliance related to induction chemotherapy. Information on compliance to treatment is registered by the treating oncologist in the patient's medical file.
13. Toxicity related to chemoradiotherapy according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Toxicity related to induction chemotherapy will be scored from day one of the first cycle until one month after the last administration of induction chemotherapy and is registered in the patient’s medical file by the treating oncologist. All CTCAE grade ≥ 2 and haematological CTCAE ≥ 3 AEs are registered.
14. Compliance related to chemoradiotherapy. Information on compliance to treatment is registered by the treating oncologist in the patient's medical file.
15. Dose reductions during induction chemotherapy are registered by the treating oncologist. The treating oncologist will record the cycle in which the dose reduction takes place and the agent for which the dose is reduced. When a dose reduction is required, the reason for dose reduction will be recorded in the patient's medical file.
16. Dose reductions during chemoradiotherapy. The treating oncologist will record a dose reduction regarding capecitabine or Teysuno. The radiation oncologist will record a dose reduction regarding radiotherapy. When dose reduction is required, the reason for dose reduction will be recorded in the patient's medical file.
17. Completion rate of induction chemotherapy: this is calculated as a percentage from the total number of patients per group.
18. Completion rate of chemoradiothearpy: this is calculated as a percentage from the total number of patients per group.
19. Surgical characteristics: data on the surgical procedure are registered in the surgical report in the patient’s medical file by the operating surgeon. Data on intraoperative radiotherapy, if administered, are registered in the patient’s medical file by the radiation oncologist.
20. Post-operative complications: data on postoperative complications, graded according to the Clavien-Dindo grading system, are registered in the patient’s medical file by the treating physician up to 3 months after surgery.
21. Quality of life questionnaires at baseline, after ICT, after CRT, 3 months, 12 months and 24 months post operatively or after entering a W&W approach. Validated quality of life questionnaires are used: QLQ-C30, QLQ-CR29, EQ-5D-5L, QLQ-CIPN-20
22. Work productivity questionnaires: WPAI-GH questionnaire at baseline, after ICT and after CRT.
23. Cost-effectiveness: the EQ-5D-5L questionnaire is used at baseline, and 12 months post-operatively.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Catharina Ziekenhuis Stichting

Sponsor organisation

Catharina Ziekenhuis Stichting

Address

Michelangelolaan 2

City

Eindhoven

Postcode

5623 EJ

Country

Netherlands

Scientific contact point

Organisation

Catharina Ziekenhuis Stichting

Contact name

J.W.A. Burger

Public contact point

Organisation

Catharina Ziekenhuis Stichting

Contact name

Evi Banken

Locations

1 EU/EEA country · 11 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 15 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications