A Phase 3 interventional study of FOLFOXIRI and CAPOX in Locally Advanced Rectal Carcinoma, sponsored by J. W. A. Burger. Recruiting at 20 sites in Netherlands. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2026-10-27.
Sponsored by J. W. A. Burger · Phase 3, Interventional, and Treatment
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.
Rationale Total neoadjuvant therapy (TNT) with induction chemotherapy (ICT) is currently considered a standard of care option for locally advanced rectal cancer (LARC) in the Dutch national guideline, primarily due to improved tumour response and a reduced risk of distant metastases (1, 2). However, the supporting evidence remains inconsistent regarding its impact on long-term oncological outcomes. While several studies using doublet-based TNT have reported higher pathological complete response rates (pCR) compared to neoadjuvant chemoradiotherapy, few have convincingly demonstrated a survival benefit (2-6). In contrast, the PRODIGE-23 trial demonstrated a survival benefit for patients treated with TNT, yet this benefit was achieved with use of a triplet chemotherapy regimen (mFOLFIRINOX) (1). In the Netherlands, triplet chemotherapy is widely used in the palliative setting. It has been shown to be more effective than doublet chemotherapy, although it is associated with increased toxicity (7-9). Although triplet chemotherapy has not yet been routinely adopted in the TNT setting, its use as part of TNT for patients with high-risk LARC has increased rapidly in recent years, despite the lack of definitive evidence supporting its superior efficacy in these patients. Patients with high-risk tumour characteristics, such as mesorectal fascia (MRF) invasion, grade IV extramural venous invasion (EMVI), tumour deposits (TD), or extensive lateral lymph node metastases (LLN), represent a subgroup with a particularly poor prognosis (10-12), referred to as high-risk LARC. It has been hypothesized that triplet-based TNT could further improve complete response rates compared with doublet-based TNT, and that patients with high-risk tumour characteristics may derive greater benefit from intensified treatment with triplet chemotherapy. Higher complete response rates may translate into improved oncological outcomes and enable organ preservation. However, whether the increased toxicity of triplet chemotherapy is justified by greater efficacy compared with doublet chemotherapy remains the key question of this trial. The primary aim of this study is to investigate whether triplet-based TNT (FOLFOXIRI) provides superior complete response rates compared with doublet-based TNT (CAPOX/FOLFOX) in patients with high-risk LARC.
Objective The objective of this study is to evaluate the effect of neoadjuvant triplet chemotherapy (FOLFOXIRI), chemoradiotherapy, and surgery or a W\&W approach (arm A) compared with neoadjuvant doublet chemotherapy (CAPOX/FOLFOX), chemoradiotherapy, and surgery or a W\&W approach (arm B) on complete response rates and oncological outcomes in patients with high-risk LARC.
Main trial endpoints The primary endpoint of this study is pCR or sustained clinical complete response (cCR) rate (defined as cCR 1 year after the last day of chemoradiotherapy).
Secondary trial endpoints Secondary endpoints of this study are regrowth rate, local recurrence rate, distant metastases rate, 3- and 5-years regrowth free survival (RFS), 3- and 5-years local recurrence free survival (LRFS), 3- and 5-years distant metastases free survival (DMFS), 3- and 5-years disease free survival (DFS), 3- and 5-years overall survival (OS), successful organ preservation at 2 years, radiological response after ICT, radiological response after chemoradiotherapy, toxicity of ICT, toxicity of chemoradiotherapy, dose reductions during ICT, dose reductions during chemoradiotherapy, completion rate of ICT, completion rate of chemoradiotherapy, the number of patients undergoing surgery, surgical characteristics, pathological response, post-operative morbidity, quality of life, work-productivity, and cost-effectiveness and -utility.
Trial design This is a national, multicentre, open-label, randomised controlled phase III trial. Patients will be randomised to receive FOLFOXIRI followed by chemoradiotherapy (arm A) or CAPOX/FOLFOX followed by chemoradiotherapy as neoadjuvant treatment (arm B). The neoadjuvant treatment will be followed by surgery or a W\&W approach.
Patients who meet the inclusion criteria but are not willing to participate in the randomised study, will be treated in accordance with the treating hospital's standard of care. If this corresponds to chemoradiotherapy, patients are asked to participate in the observational cohort (registration arm).
Trial population Patient with non-metastasised, LARC with the presence of at least one high-risk tumour characteristic: MRF invasion, EMVI grade IV, TD, bilateral or extensive enlarged LLN. Patients are required to have a WHO performance status of 0-1 and no contra-indications for the planned neoadjuvant treatment.
Interventions In arm A, patients receive neoadjuvant FOLFOXIRI and chemoradiotherapy as neoadjuvant treatment, followed by surgery or a W\&W approach. In arm B, patients receive neoadjuvant CAPOX/FOLFOX and chemoradiotherapy as neoadjuvant treatment, followed by surgery or a W\&W approach. Restaging with a pelvic MRI and CT-scan will be performed after 3 or 4 cycles of ICT. Patients with stable or responsive disease receive additional 1 or 2 cycles ICT and continue with neoadjuvant chemoradiotherapy, followed by surgery or a W\&W approach. In the observational cohort, patients receive chemoradiotherapy as neoadjuvant treatment, followed by surgery or a W\&W approach. First restaging with a pelvic MRI and CT-scan will be performed 6-8 weeks after the last day of chemoradiotherapy. In case of a good or complete response, an endoscopy is performed ≤ 2 weeks and second restaging is planned 14-16 weeks after the last day of chemoradiotherapy. Patients with an incomplete response and resectable disease at first restaging will undergo surgery 10-14 weeks after the last day of chemoradiotherapy. Patients with a good or (near) complete response at second restaging (14-16 weeks) will undergo a third restaging at 26 weeks after the last day of chemoradiotherapy. If a cCR is achieved at that time, patients continue follow-up in a watch-and-wait approach (W\&W). Patients with no further improvement in response (sustained incomplete response) will proceed to TME-surgery. In highly selected patients with an ongoing good, but not complete response, a TAMIS can be considered if technically feasible as alternative for TME-surgery.
Ethical considerations relating to the clinical trial including the expected benefit to the individual subject or group of patients represented by the trial subjects as well as the nature and extent of burden and risks The potential benefits of participation in this trial include a higher likelihood of achieving a complete tumour response, which may allow for organ-preserving treatment strategies and thereby improve quality of life. Enhanced tumour regression could also translate into better long-term oncological outcomes, such as improved disease-free and OS. However, these potential benefits must be weighed against the increased toxicity associated with triplet chemotherapy.
Trial-specific risk is limited. The investigational medicinal product has a well-documented and established safety profile and, is in broad use in the palliative setting, proved safe in the phase II MEND-IT trial and is increasingly being used in the neoadjuvant setting. It will be used in the authorised form for its authorised indication. The primary risk associated with participating in the trial is increased toxicity related to the use of ICT, compared to chemoradiotherapy alone. To mitigate this risk, only patients who are deemed fit to receive FOLFOXIRI, with a WHO performance status of 0-1, are eligible for inclusion. The national multidisciplinary writing committee and the Dutch Colorectal Cancer Group anticipate that the potential benefits of the trial outweigh the associated risks. Trial-specific burden is minimal, as it is limited to completing quality of life questionnaires. Participation in these questionnaires is optional, as they pertain to secondary outcome measures.
138 studies on the registry are indexed under Pathologic Complete Response; 57 are open to participants now.
This study's planned enrollment of 394 is above the median of 85 across 92 interventional studies indexed under Pathologic Complete Response.
Browse Pathologic Complete Response studies →This is the only study on the registry with J. W. A. Burger as lead sponsor.
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Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
Confirmed high-risk locally advanced rectal cancer, at high risk of treatment failure, meeting one of the following imaging-based criteria:
Exclusion Criteria:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Neoadjuvant treatment is given before the main treatment (usually surgery), often to shrink a tumour. Adjuvant treatment is given after it, to lower the chance of the cancer coming back.
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Cancer that has spread from where it began to other parts of the body. “Metastatic” cancer is cancer that has spread this way.
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
Malignancy means cancer. Criteria about another or earlier malignancy ask whether you have had a different cancer, usually within a set number of years.
Some are commonly allowed, such as treated skin cancers other than melanoma and early cancers removed completely — check the exceptions this study lists.
Adjuvant and neoadjuvant
Neoadjuvant treatment is given before the main treatment (usually surgery), often to shrink a tumour. Adjuvant treatment is given after it, to lower the chance of the cancer coming back.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Metastases
Cancer that has spread from where it began to other parts of the body. “Metastatic” cancer is cancer that has spread this way.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Contraindication
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Cancer (malignancy)
Malignancy means cancer. Criteria about another or earlier malignancy ask whether you have had a different cancer, usually within a set number of years.
Some are commonly allowed, such as treated skin cancers other than melanoma and early cancers removed completely — check the exceptions this study lists.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Triplet induction chemotherapy (FOLFOXIRI) followed by chemoradiotherapy and surgery or a watch-and-wait approach.
Drug: FOLFOXIRI · Radiation: Chemoradiotherapy · Procedure: Total mesorectal excision (+/- IORT) · Diagnostic Test: Watch-and-wait approach
Doublet induction chemotherapy (FOLFOXIRI) followed by chemoradiotherapy and surgery or a watch-and-wait approach.
Drug: CAPOX · Drug: FOLFOX (5-fluorouracil, Leucovorin, Oxaliplatin) · Radiation: Chemoradiotherapy · Procedure: Total mesorectal excision (+/- IORT) · Diagnostic Test: Watch-and-wait approach
A 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.
Radiation: Chemoradiotherapy · Procedure: Total mesorectal excision (+/- IORT) · Diagnostic Test: Watch-and-wait approach
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.
Also known as: Triplet, Induction chemotherapy, Total neoadjuvant therapy, 5-FU, 5-fluorouracil, Irinotecan, Leucovorin, Oxaliplatin
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.
Also known as: Doublet, Induction chemotherapy, Total neoadjuvant therapy, Capecitabine, Oxaliplatin
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.
Also known as: Doublet, Induction chemotherapy, 5-FU, 5-fluorouracil, Leucovorin, Oxaliplatin
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.
Also known as: Capecitabine, Radiation, Teysuno
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.
Also known as: TME, Low Anterior Resection, LAR, Abdominoperineal Rectal Amputation, APR, Intra-operative Radiotherapy, IORT, Radiation
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.
Also known as: W&W, Endoscopy, Magnetic Resonance Imaging, MRI, Colonoscopy, Computer Tomography, CT
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.
Time frame: pCR: date of surgery sustained cCR: from date of surgery or date of entering a watch-and-wait approach, up until 1 year later.
Regrowth free survival
To compare long term oncological outcomes at 3- and 5 years between neoadjuvant FOLFOXIRI and neoadjuvant CAPOX/FOLFOX, including regrowth free survival.
Time frame: 3 and 5 years post-treatment.
Local recurrence free survival at 3 and 5 years
To compare long term oncological outcomes at 3- and 5 years between neoadjuvant FOLFOXIRI and neoadjuvant CAPOX/FOLFOX, including local recurrence free survival.
Time frame: 3 and 5 years post-treatment
Distant metastasis free survival
To compare long term oncological outcomes at 3- and 5 years between neoadjuvant FOLFOXIRI and neoadjuvant CAPOX/FOLFOX, including distant metastasis free survival.
Time frame: 3 and 5 years post-treatment.
Progression free survival
To compare long term oncological outcomes at 3- and 5 years between neoadjuvant FOLFOXIRI and neoadjuvant CAPOX/FOLFOX, including progression free survival.
Time frame: 3 and 5 years post-treatment.
Disease free survival (DFS)
To compare long term oncological outcomes at 3- and 5 years between neoadjuvant FOLFOXIRI and neoadjuvant CAPOX/FOLFOX, including disease free survival.
Time frame: 3 and 5 years post-treatment
Overall survival
To compare long term oncological outcomes at 3- and 5 years between neoadjuvant FOLFOXIRI and neoadjuvant CAPOX/FOLFOX, including overall survival.
Time frame: 3 and 5 years post-treatment
Successful organ preservation
Organ preservation, defined as no bowel resection or stoma placement at 1 and 3 years follow-up.
Time frame: 1 and 3 years post-treatment
Radiological response
To compare radiological response between neoadjuvant FOLFOXIRI and neoadjuvant CAPOX/FOLFOX.
Time frame: At baseline, after induction chemotherapy (= approximately 12-14 weeks after enrollment), and after chemoradiotherapy (= approximately 20-28 weeks after enrollment).
Pathological response
To compare pathological response between neoadjuvant FOLFOXIRI and neoadjuvant CAPOX/FOLFOX.
Time frame: Date of surgery.
Toxicity, compliance and dose reductions of ICT and CRT
To compare toxicity related to ICT between neoadjuvant FOLFOXIRI and neoadjuvant CAPOX/FOLFOX (toxicity, compliance and dose reductions during both ICT and CRT).
Time frame: From onset of ICT up until 3 months after last radiation (= approximately 8-10 months after enrollment).
Completion rates of ICT and CRT
To compare the completion rates of ICT and chemoradiotherapy, both separately and combined, between neoadjuvant FOLFOXIRI and neoadjuvant CAPOX/FOLFOX. Calculated as a percentage from the total number of patients per group.
Time frame: From onset of ICT up until last radiation (=approximately 20-28 weeks after enrollment).
Number of patients undergoing surgery
To compare the number of patients undergoing surgery between neoadjuvant FOLFOXIRI and neoadjuvant CAPOX/FOLFOX, calculated as a percentage from the total number of patients per group.
Time frame: At surgery date.
Surgical characteristics and post-operative morbidity
To compare surgical characteristics and post-operative morbidity between neoadjuvant FOLFOXIRI and neoadjuvant CAPOX/FOLFOX. 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. 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 (44).
Time frame: At surgery date up until 3 months after surgery.
Patient-reported quality of life measured by the QLQ-C30 questionnaire
\* Quality of Life Questionnaire - Core 30 (QLQ-C30) * Questions regarding general symptoms and functional impairments with an answering scale ranging from 'Not at all' to 'A lot'; a higher score meaning worse quality of life; * Questions regarding patient-reported quality of life in general with an answering scale ranging from 'Very bad' to 'Excellent'; a higher score meaning better quality of life.
Time frame: At baseline, after induction chemotherapy (= approximately 12-14 weeks after enrollment), after chemoradiotherapy (= approximately 20-28 weeks after enrollment), and 3 - 12 - 24 months after surgery or entering a Watch-and-Wait approach.
Patient-reported quality of life measured by the QLQ-CR29 questionnaire
Quality of Life Questionnaire - Colorectal cancer module 29 (QLQ-CR29): Questions regarding disease-specific symptoms with an answering scale ranging from 'Not at all' to 'A lot'; a higher score meaning worse quality of life;
Time frame: At baseline, after induction chemotherapy (= approximately 12-14 weeks after enrollment), after chemoradiotherapy (= approximately 20-28 weeks after enrollment), and 3 - 12 - 24 months after surgery or entering a Watch-and-Wait approach.
Patient-reported quality of life measured by the QLQ-CIPN-20 questionnaire.
Quality of Life Questionnaire - Chemotherapy-Induced Peripheral Neuropathy (QLQ-CIPN-20): questions regarding chemotherapy-specific symptoms with an answering scale ranging from 'Not at all' to 'A lot'; a higher score meaning worse quality of life.
Time frame: At baseline, after induction chemotherapy (= approximately 12-14 weeks after enrollment), after chemoradiotherapy (= approximately 20-28 weeks after enrollment), and 3 - 12 - 24 months after surgery or entering a Watch-and-Wait approach.
Patient-reported quality of life, measured by the EQ-5D-5L questionnaire.
EuroQoL 5 Dimensions, 5 Levels (EQ-5D-5L) * Questions regarding general symptoms and functional impairments on a scale of ranging from 'No problems' to 'Not able to ... at all), a higher score meaning worse quality of life. * Scale ranging from worst to best health imagineable, a higher score meaning better quality of life.
Time frame: At baseline, after induction chemotherapy (= approximately 12-14 weeks after enrollment), after chemoradiotherapy (= approximately 20-28 weeks after enrollment), and 3 - 12 - 24 months after surgery or entering a Watch-and-Wait approach.
Patient-reported work productivity/activity impairment (measured by WPAI-GH questionnaires)
Measured by the Work Productivity and Activity Impairment - General Health (WPAI-GH) questionnaire version 2, comprised of questions with a numeric answer (e.g., number of hours of absence from occupation in the last 7 days), and scales regarding impact of health on work productivity and activity impairment, ranging from 'no impact' to 'total impediment of doing my job'; on these scales, a higher score means greater activity impairment.
Time frame: At baseline, after induction chemotherapy (= approximately 12-14 weeks after enrollment), and after chemoradiotherapy (= approximately 20-28 weeks after enrollment)
Cost-effectiveness and -utility
To compare cost-effectiveness and -utility between neoadjuvant FOLFOXIRI and neoadjuvant CAPOX/FOLFOX. For the purpose of economic evaluation, the EQ-5D-5L questionnaire (see description below) is used at baseline, and 12 months post-operatively. \* EuroQoL 5 Dimensions, 5 Levels (EQ-5D-5L) * Questions regarding general symptoms and functional impairments on a scale of ranging from 'No problems' to 'Not able to ... at all), a higher score meaning worse quality of life. * Scale ranging from worst to best health imagineable, a higher score meaning better quality of life.
Time frame: From enrollment up until 1 year post-operatively or after entering a W&W approach.
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Plan to share: Undecided
Started Mar 2026 (actual). Primary completion is estimated for Mar 2030, 47 months after the start.
How these figures are worked out, and which studies are left out of them.
From the registry record's own update history. This site started tracking changes on Sep 25, 2026; for anything earlier, see the record history on ClinicalTrials.gov ↗
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