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Induction Chemotherapy for Locally Advanced Rectal Cancer (MEND-IT)

Primary Purpose

Rectal Cancer

Status

Not yet recruiting

Phase

Phase 2

Locations

Netherlands

Study Type

Interventional

Intervention

FOLFOXIRI Protocol

About this trial

This is an interventional treatment trial for Rectal Cancer focused on measuring Locally advanced rectal cancer, Induction chemotherapy, Neoadjuvant chemotherapy, Chemoradiotherapy

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

18 years or older
WHO performance score 0-1.
Histopathologically confirmed rectal cancer.
Lower border of the tumour located below the sigmoidal take-off as established on MRI of the pelvis.
Confirmed high-risk locally advanced rectal cancer, meeting one of the following imaging based criteria:
- Tumour invasion of mesorectal fascia (MRF+)
- The presence of grade 4 extramural venous invasion (mrEMVI)
- The presence of tumour deposits (TD)
- The presence of Extramesorectal lymph nodes with a short-axis size > 7mm (LNN)
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 S3 and upwards are considered not resectable • Written informed consent.

Exclusion Criteria:

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.
Radiotherapy in the pelvic area within the past 6 months.
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.

Sites / Locations

Catharina Hospital Eindhoven
Netherlands Cancer Institute
Maastricht University Medical Centre
Radboud University Medical Centre
Erasmus MC Cancer institute
University Medical Centre
Isala hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Single-arm study

Arm Description

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Number of patients undergoing surgery.

This is calculated as a percentage from the total number of patients that were included.

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.

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.

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.

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.

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.

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.

Full Information

NCT ID

NCT04838496

First Posted

April 2, 2021

Last Updated

April 6, 2021

Sponsor

Catharina Ziekenhuis Eindhoven

1. Study Identification

Unique Protocol Identification Number

NCT04838496

Brief Title

Induction Chemotherapy for Locally Advanced Rectal Cancer

Acronym

MEND-IT

Official Title

Neo-adjuvant FOLFOXIRI and Chemoradiotherapy for High Risk ("Ugly") Locally Advanced Rectal Cancer

Study Type

Interventional

2. Study Status

Record Verification Date

April 2021

Overall Recruitment Status

Not yet recruiting

Study Start Date

June 1, 2021 (Anticipated)

Primary Completion Date

June 1, 2025 (Anticipated)

Study Completion Date

June 1, 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Catharina Ziekenhuis Eindhoven

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief 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. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Rectal Cancer

Keywords

Locally advanced rectal cancer, Induction chemotherapy, Neoadjuvant chemotherapy, Chemoradiotherapy

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Model Description

This is a multicentre, single-arm, prospective phase 2 study.

Masking

None (Open Label)

Allocation

N/A

Enrollment

128 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Single-arm study

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

FOLFOXIRI Protocol

Intervention Description

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.

Primary Outcome Measure Information:

Title

Description

Time Frame

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 Outcome Measure Information:

Title

3-year and 5-year local recurrence free survival.

Description

ocal recurrence is confirmed by either radiological or histopathological examination. A recurrence is registered by the treating physician in the patient's medical file.

Time Frame

3 and 5 year

Title

3-year and 5-year distant metastasis free survival.

Description

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.

Time Frame

3 and 5 year

Title

3-year and 5-year progression free survival.

Description

Time Frame

3 and 5 year

Title

3-year and 5-year disease free survival.

Description

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.

Time Frame

3 and 5 year

Title

3-year and 5-year overall survival.

Description

Mortality is registered in the patient's medical file which is linked to the municipal personal records database.

Time Frame

3 and 5 year

Title

Radiological response after induction therapy.

Description

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.

Time Frame

Directly after induction chemotherapy

Title

Radiological response after chemoradiotherapy.

Description

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.

Time Frame

6-8 weeks after chemoradiotherapy

Title

Pathologic response

Description

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.

Time Frame

Directly after surgery

Title

Toxicity related to induction therapy.

Description

Time Frame

During induction chemotherapy

Title

The induction therapy compliance rate.

Description

Time Frame

During induction chemotherapy

Title

Toxicity of chemoradiotherapy.

Description

Time Frame

During chemoradiotherapy

Title

The compliance rate related to chemoradiotherapy.

Description

Time Frame

During chemoradiotherapy

Title

Number of patients undergoing surgery.

Description

This is calculated as a percentage from the total number of patients that were included.

Time Frame

immediately after surgery

Title

Type of surgery, including the use of intra-operative radiotherapy.

Description

Time Frame

During the surgical procedure

Title

Major surgical morbidity rate

Description

Time Frame

During admission for surgery.

Title

Generic and cancer-specific Quality of life (QoL) assessments during treatment using Quality of life Questionnaires (QLQ)

Description

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.

Time Frame

At the moment of inclusion, after 3 months and after 12 months.

Title

Generic and cancer-specific Quality of life (QoL) assessments during treatment

Description

Time Frame

At the moment of inclusion, after 3 months and after 12 months.

Title

Generic and cancer-specific Quality of life (QoL) assessments during treatment

Description

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.

Time Frame

At the moment of inclusion, after 3 months and after 12 months.

Title

Costs

Description

Time Frame

At the moment of inclusion, after 3 months and after 12 months.

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: 18 years or older WHO performance score 0-1. Histopathologically confirmed rectal cancer. Lower border of the tumour located below the sigmoidal take-off as established on MRI of the pelvis. Confirmed high-risk locally advanced rectal cancer, meeting one of the following imaging based criteria: Tumour invasion of mesorectal fascia (MRF+) The presence of grade 4 extramural venous invasion (mrEMVI) The presence of tumour deposits (TD) The presence of Extramesorectal lymph nodes with a short-axis size > 7mm (LNN) 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 S3 and upwards are considered not resectable • Written informed consent. Exclusion Criteria: 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. Radiotherapy in the pelvic area within the past 6 months. 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.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Kim van den Berg, MD

Phone

040-2396641

kim.vd.berg@catharinaziekenhuis.nl

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Pim J.W.A. Burger, MD. PhD.

Organizational Affiliation

Catharina Ziekenhuis Eindhoven

Official's Role

Principal Investigator

Facility Information:

Facility Name

Catharina Hospital Eindhoven

City

Eindhoven

State/Province

Noord-Brabant

Country

Netherlands

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Pim Burger, MD/PhD

pim.burger@catharinaziekenhuis.nl

Facility Name

Netherlands Cancer Institute

City

Amsterdam

State/Province

Noord-Holland

Country

Netherlands

Facility Name

Maastricht University Medical Centre

City

Maastricht

Country

Netherlands

Facility Name

Radboud University Medical Centre

City

Nijmegen

Country

Netherlands

Facility Name

Erasmus MC Cancer institute

City

Rotterdam

Country

Netherlands

Facility Name

University Medical Centre

City

Utrecht

Country

Netherlands

Facility Name

Isala hospital

City

Zwolle

Country

Netherlands

12. IPD Sharing Statement

Citations:

PubMed Identifier

36068495

Citation

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.

Results Reference

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Induction Chemotherapy for Locally Advanced Rectal Cancer

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