Rectal CancerPhase 2MEND-ITNCT04838496
Induction Chemotherapy for Locally Advanced Rectal Cancer
A Phase 2 study testing FOLFOXIRI Protocol in people with Rectal Cancer, run by Catharina Ziekenhuis Eindhoven at 13 sites in Netherlands.
Trial summary
Despite developments in the multidisciplinary treatment of patients with locally advanced rectal cancer (LARC), such as the introduction of total mesorectal excision (TME) by Heald et al. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Rectal Cancer
- What is being tested?
- FOLFOXIRI Protocol
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 128 participants
- Where
- 13 sitesNetherlands
- Study dates
- 3 Nov 2021to 1 Aug 2031
- Phase
- Phase 2
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 18 years or older
- WHO performance score 0-1.
- Fit for (modified dose) triple chemotherapy (FOLFOXIRI)
- Histopathologically 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:
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- Tumour invasion of mesorectal fascia (MRF+)
- 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 ischiadic nerve and invasion of the cortex from S2 and upwards are considered not resectable • Written informed consent.
Who cannot join
- Evidence of metastatic disease at the moment of inclusion or within six months prior to inclusion except for patients with enlarged iliac or inguinal lymph nodes and aspecific lung noduli.
- Homozygous DPD (Dihydropyrimidine dehydrogenase) deficiency.
- Any chemotherapy within the past 6 months.
- o 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.
Trial locations and contacts
13 sites in 1 country.
13 sites in 1 country
Netherlands13 sites
Netherlands Cancer Institute
Amsterdam, North Holland
Amsterdam UMC, location VUmc
Amsterdam
Catharina Hospital Eindhoven
Eindhoven, North Brabant
Anna Hospital
Geldrop
Elkerliek Hospital
Helmond
Maastricht University Medical Centre
Maastricht
Maastro Clinic
Maastricht
Radboud University Medical Centre
Nijmegen
Erasmus MC Cancer institute
Rotterdam
University Medical Centre
Utrecht
Maxima Medical Centre
Veldhoven
St. Jans Gasthuis
Weert
Isala hospital
Zwolle
About this study
Official title: Neo-adjuvant FOLFOXIRI and Chemoradiotherapy for High Risk ("Ugly") Locally Advanced Rectal Cancer
Despite developments in the multidisciplinary treatment of patients with locally advanced rectal cancer (LARC), such as the introduction of total mesorectal excision (TME) by Heald et al. and the shift from adjuvant to neoadjuvant (chemo)radiotherapy ((C)RT), local and distant recurrence rates remain between 5-10% and 25-40% respectively. Several studies established tumour characteristics with particularly bad prognosis; it was demonstrated that the occurrence of mesorectal fascia involvement (MRF+), grade 4 extramural venous invasion (EMVI), tumour deposits (TD) and enlarged lateral lymph nodes (LLN) lead to high local and distant recurrence rates and decreased survival when compared with LARC without these particularly negative prognostic factors. This type of LARC is described as high risk LARC (hr-LARC). Achieving a resection with clear resection margins (R0) is an important prognostic factor for local (LR) and distant recurrence (DM) as well as survival. With the aim to further reduce the risk of recurrent rectal cancer, to diminish distant metastasis and to improve overall survival for patients with LARC, induction chemotherapy (ICT) became a growing area of research. The addition of ICT has the ability to induce more local tumour downstaging, possibly leading to resectability of previously unresectable tumours, more R0 resections and less extensive surgery. In the case of a complete clinical response, surgery may even be omitted. ICT may also have the potential to eradicate micrometastases. Hence, increased local downstaging and reducing distant metastatic spread may reduce LR and DM rates and improve survival and quality of life. In recent years, the use of ICT was investigated and showed promising results, but little is known about the addition of ICT in patients with high risk LARC. Since these patients have a particularly bad prognosis, both with regard to locoregional and distant failure, a more intensified neoadjuvant treatment with FOLFOXIRI is anticipated to improve short- and long term results.
- Conditions
- Rectal Cancer
- Being tested
- FOLFOXIRI Protocol
- Keywords
- Locally advanced rectal cancer, Induction chemotherapy, Neoadjuvant chemotherapy, Chemoradiotherapy
- Medical subject headings
- Rectal Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
FOLFOXIRI ProtocolDrug
FOLFOXIRI consists of oxaliplatin, irinotecan, leucovorin and 5-fluorouracil and is administered every 2 weeks:
Dosing:
- 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.
Both regimen are initially administered for four cycles. In case of responsive or stable disease, a 5th and 6th cycle of FOLFOXIRI will be administered.
In case of unacceptable toxicity, the aforementioned dosages can be reduced or one or more chemotherapeutical agents can be omitted at discretion of the medical oncologist and will be noted in the patient's medical file. At discretion of the medical oncologist, a start dosage of 75% of the advised dosage could be considered in patients above 70 years of age.
| Study group | Role | What they receive |
|---|---|---|
| Single-arm study | Experimental | All patients will receive induction chemotherapy consisting of 4-6 cycles of FOLFOXIRI. Restaging will be performed after 4 cycles with a pelvic MRI and a thoraco-abdominal CT-scan. In case of stable or responsive disease, the remaining 2 cycles of FOLFOXIRI will be provided. In case of progressive, but still resectable disease, chemoradiation will be provided immediately, without the remaining 2 cycles of FOLFOXIRI. Restaging will be performed after chemoradiation. In case of resectable disease, surgery is performed. Receives: Drug: FOLFOXIRI Protocol |
What is being measured
The primary outcome is the main question the study is designed to answer.
The main study parameter is the proportion of patients with a pathological complete response (pCR) and those patients who started a wait and see strategy and have sustained clinical complete response (cCR) at 1 year.
The pCR is evaluated by an experienced pathologist. A pCR is defined as the absence of residual tumour cells in the complete resected specimen including all resected regional lymph nodes (ypT0N0). A cCR is defined as the absence of viable tumour tissue based on MRI, evaluated by an experienced radiologist. There is a cCR in case of a sustained clinical response at 1 year after chemoradiotherapy.
Measured: pCR is determined after surgery directly. There is a cCR in case of a sustained clinical response until at least one year after chemoradiotherapy
Secondary outcomes (19)
3-year and 5-year local recurrence free survival.
ocal recurrence is confirmed by either radiological or histopathological examination. A recurrence is registered by the treating physician in the patient's medical file.
Measured: 3 and 5 year
3-year and 5-year distant metastasis free survival.
Distant metastases may be confirmed by either radiological or histopathological examination. Data on distant metastases are registered by the treating physician in the patient's medical file.
Measured: 3 and 5 year
3-year and 5-year progression free survival.
Progression is defined as progression of the primary tumour, local recurrence, distant metastases confirmed by radiological or histopathological examination or death. Data regarding disease progression are registered by the treating physician in the patient's medical file.
Measured: 3 and 5 year
3-year and 5-year disease free survival.
Disease free survival is defined as no confirmed recurrence, distant metastases or death. Disease recurrence is registered by the treating physician in the patient's medical file.
Measured: 3 and 5 year
3-year and 5-year overall survival.
Mortality is registered in the patient's medical file which is linked to the municipal personal records database.
Measured: 3 and 5 year
Radiological response after induction therapy.
Assessment and reporting of all MRI scans is performed according to a standard operating procedure and is registered in the patient file by the radiologist.
Measured: Directly after induction chemotherapy
Radiological response after chemoradiotherapy.
Assessment and reporting of all MRI scans is performed according to a standard operating procedure and is registered in the patient file by the radiologist.
Measured: 6-8 weeks after chemoradiotherapy
Pathologic response
The pathologic response is graded according to the Mandard grading system. The Mandard grading is registered by the pathologist in the pathology report in the patient's medical file.
Measured: Directly after surgery
Toxicity related to induction therapy.
Systemic related toxicity is graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Toxicity caused by induction therapy will be scored from day one of the first cycle of induction therapy until one month after the last administration of the induction therapy and is registered in the patient's medical file by the treating medical oncologist. Only all non-hematologic NCI-CTCAE grade 3-4 and all NCI-CTCAE ≥4 are registered.
Measured: During induction chemotherapy
The induction therapy compliance rate.
Information on completion of induction therapy is registered by the treating medical oncologist. In all patients in whom a dose reduction is required the reason for dose reduction will be recorded in the patient's medical file.
Measured: During induction chemotherapy
Toxicity of chemoradiotherapy.
Chemoradiotherapy related toxicity is graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Toxicity caused by chemoradiotherapy will be scored from start of radiotherapy until 3 months after the last administration of the radiotherapy and is registered in the patient's medical file by the treating radiation oncologist. Only all non-hematologic NCI-CTCAE grade 3-4 and all NCI-CTCAE ≥4 are registered.
Measured: During chemoradiotherapy
The compliance rate related to chemoradiotherapy.
Information on completion of chemoradiotherapy is registered by the treating radiation oncologist and registered in the patient's medical file. In all patients in whom a dose reduction is required the reason for dose reduction will be recorded in the patient's medical file.
Measured: During chemoradiotherapy
Number of patients undergoing surgery.
This is calculated as a percentage from the total number of patients that were included.
Measured: immediately after surgery
Type of surgery, including the use of intra-operative radiotherapy.
Directly after surgery, information with respect to procedure related characteristics is registered in the surgical report in the patient's medical file by the operating surgeon. Data on intra-operative radiotherapy, if administered, are registered in the patient's medical file by the treating radiation oncologist.
Measured: During the surgical procedure
Major surgical morbidity rate
Surgical complications are graded according to the Clavien-Dindo grading system. Complications will be scored up to 3 months after surgery and are registered in the patient file by the treating physician.
Measured: During admission for surgery.
Generic and cancer-specific Quality of life (QoL) assessments during treatment using Quality of life Questionnaires (QLQ)
Generic and cancer-specific quality of life assessments are assessed with QLQ-C30, a 4 point scale. Higher scores correspond with a higher response level.
Measured: At the moment of inclusion, after 3 months and after 12 months.
Generic and cancer-specific Quality of life (QoL) assessments during treatment
Generic and cancer-specific quality of life assessments are assessed with QLQ-CR29, a 4 point scale. Higher scores represent better functioning on functional scales and a higher level of symptoms on the symptom scale.
Measured: At the moment of inclusion, after 3 months and after 12 months.
Generic and cancer-specific Quality of life (QoL) assessments during treatment
Generic and cancer-specific quality of life assessments are assessed with EQ-5D-5L, a 5 point scale. Higher scores corresponds with a higher level of symptoms on the symptom scale.
Measured: At the moment of inclusion, after 3 months and after 12 months.
Costs
For the purpose of economic evaluation, the EQ-5D-5L questionnaire is used at inclusion and at 3 and 12 months post-operatively. The questionnaires will be sent either by mail or digitally, according to the patient's preference.
Measured: At the moment of inclusion, after 3 months and after 12 months.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Apr 2021
- Study start3 Nov 2021
- Primary completion1 Aug 2026
- Study completion1 Aug 2031 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Rectal CancerStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Model description
- This is a multicentre, single-arm, prospective phase 2 study.
- Masking
- None (open label)
- Enrolment
- 128 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Catharina Ziekenhuis Eindhoven
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, J. W. A. Burger, Catharina Ziekenhuis Eindhoven
- Investigators
- Jacobus W.A. Burger, MD. PhD., Principal investigator, Catharina Ziekenhuis Eindhoven
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04838496
- Sponsor's protocol ID
- NL74465.100.20
- Acronym
- MEND-IT
- Status last verified
- Oct 2026
- First submitted
- 2 Apr 2021
- Last updated
- 23 Oct 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
van den Berg K, Schaap DP, Voogt ELK, Buffart TE, Verheul HMW, de Groot JWB, Verhoef C, Melenhorst J, Roodhart JML, de Wilt JHW, van Westreenen HL, Aalbers AGJ, van 't Veer M, Marijnen CAM, Vincent J, Simkens LHJ, Peters NAJB, Berbee M, Werter IM, Snaebjornsson P, Peulen HMU, van Lijnschoten IG, Roef MJ, Nieuwenhuijzen GAP, Bloemen JG, Willems JMWE, Creemers GJM, Nederend J, Rutten HJT, Burger JWA. Neoadjuvant FOLFOXIRI prior to chemoradiotherapy for high-risk ("ugly") locally advanced rectal cancer: study protocol of a single-arm, multicentre, open-label, phase II trial (MEND-IT). BMC Cancer. 2022 Sep 6;22(1):957. doi: 10.1186/s12885-022-09947-w.
PubMed 36068495