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Total Neoadjuvant Therapy of SCRT+CAPOX vs SCRT+CAPOXIRI for Locally Advanced Rectal Cancer (ENSEMBLE) (ENSEMBLE)

Primary Purpose

Locally Advanced Rectal Cancer

Status
Recruiting
Phase
Phase 3
Locations
Japan
Study Type
Interventional
Intervention
SCRT
CAPOX
CAPOXIRI
Sponsored by
National Cancer Center Hospital East
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Locally Advanced Rectal Cancer focused on measuring Radiation, CAPOXIRI, CAPOX, Rectal cancer, Total neoadjuvant therapy, Rectal Neoplasms, Colorectal Neoplasms, Intestinal Neoplasms, Gastrointestinal Neoplasms, Digestive System Neoplasms, Capecitabine, Oxaliplatin, Irinotecan, Antineoplastic Agents, Chemotherapy, Non-operative management, Surgery, MRI, Restaging, QOL, Organ preservation

Eligibility Criteria

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

Inclusion Criteria: The content of this research was fully explained, and written informed consent was obtained from the subject. Histologically confirmed rectal adenocarcinoma. Radical resection is clinically possible without any distant metastases on imaging studies. Age of 18 years or older on the date of consent acquisition. Eastern Cooperative Oncology Group (ECOG) PS 0-1 (PS 0 if aged 70 years or older on consent acquisition date). Inferior margin of the tumor is within 12 cm of the AV. No prior tumor treatment. No history of radiation therapy to the pelvis, including treatment for other cancer types. Cases with cT3-4N0M0*or T1-4N1-2M0 based on Union Internationale Contre le Cancer (UICC) 8th edition. (*5 cm< AV ≤ 10 cm, T3a/bN0M0, extramural venous invasion (EMVI) -, mesorectal fascia (MRF) clear and 10 cm < AV ≤ 12 cm, T3a/bN0-1M0, EMVI-, MRF clear are eligible only for those who refused surgery) UGT1A1 is wild-type or single heterozygous. Criteria for major organ function within 28 days prior to enrollment. If there are multiple test results within this period, the most recent one will be used, and blood transfusions and hematopoietic factor preparations will not be administered within 14 days before the test date for measurements before registration. Neutrophil count: ≥1,500/mm3 Platelet count: ≥10.0×10 4/mm3 Hemoglobin concentration: ≥9.0 g/dL Total bilirubin: ≤2.0 mg/dL Aspartate transaminase (AST): ≤100 IU/L or less Alanine transaminase (ALT): ≤100 IU/L or less Serum creatinine: Creatinine clearance ≥30 mL/min (by Cockcroft & Gault formula) Exclusion Criteria: Extensive surgery (excluding colostomy and central venous port construction) within 4 weeks before starting protocol treatment. Complications or history of severe lung disease (such as interstitial pneumonia, pulmonary fibrosis, and severe emphysema). Colonic stent in place. Contraindications for MRI such as cardiac pacemakers. Serious comorbidities (such as heart failure, renal failure, liver failure, intestinal paralysis, intestinal obstruction, uncontrolled diabetes, and active inflammatory bowel disease). Patients with multiple active cancers (simultaneous multiple cancers or metachronous multiple cancers with a disease-free interval of 5 years or less). However, carcinoma in situ or lesions equivalent to intramucosal carcinoma, which can be cured by local treatment, are not treated as active multiple cancers. Pregnant women, lactating women, positive pregnancy test, or unwillingness to use contraception. Hepatitis B surface (HBs) antigen positive or hepatitis C virus (HCV) antibody-positive. However, HCV-RNA-negative can be registered. Have human immunodeficiency virus (HIV) infection. MSI-high (MSI-H) or defective mismatch repair (dMMR) is known. Unwilling to donate specimens for "Research on gene profiling and clinical significance using clinical specimens from cancer patients" for whole-genome analysis based on the "Action Plan for Whole-Genome Analysis, etc." (CONDUCTOR study). Any other patients the principal investigator or co-investigator deems inappropriate for study participation.

Sites / Locations

  • National Cancer Center Hospital EastRecruiting
  • Kyushu University HospitalRecruiting
  • National Hospital Organization Kyushu Cancer CenterRecruiting
  • National Hospital Organization Kyushu Medical CenterRecruiting
  • Gifu University HospitalRecruiting
  • Hirosaki University HospitalRecruiting
  • Hiroshima University HospitalRecruiting
  • St. Marianna University HospitalRecruiting
  • University of Occupational and Environmental Health HospitalRecruiting
  • Nagoya University HospitalRecruiting
  • Ohara Memorial Kurashiki Central Medical Organization Kurashiki Central HospitalRecruiting
  • Kindai University HospitalRecruiting
  • National Hospital Organization Osaka Medical CenterRecruiting
  • Osaka Prefectural Hospital Organization Osaka Acute and General Medical CenterRecruiting
  • Osaka University HospitalRecruiting
  • Kitasato University HospitalRecruiting
  • Sapporo Medical University HospitalRecruiting
  • Foundation for Cancer Research Ariake HospitalRecruiting
  • Keio University HospitalRecruiting
  • National Cancer Center HospitalRecruiting
  • Nippon Medical School HospitalRecruiting
  • Tokyo Metropolitan Hospital Organization Tokyo Metropolitan Komagome HospitalRecruiting
  • Kanagawa Prefectural Hospital Organization Kanagawa Cancer CenterRecruiting
  • Yokohama City University HospitalRecruiting
  • Yokohama City University Medical CenterRecruiting
  • Federation of National Public Service Personnel Mutual Aid Associations Yokosuka Mutual Aid HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Experimental

Arm Label

Control arm SCRT+CAPOX

Experimental arm SCRT+CAPOXIRI

Arm Description

The standard-of-care group receives short-course radiation therapy (5 × 5 Gy) followed by six cycles of CAPOX (capecitabine 1000 mg/m2 orally twice daily on days 1-14, oxaliplatin 130 mg/m2 intravenously on day 1, q3wks).

The standard-of-care group receives short-course radiation therapy (5 × 5 Gy) followed by six cycles of CAPOX (capecitabine 1000 mg/m2 orally twice daily on days 1-14, oxaliplatin 130 mg/m2 intravenously on day 1, q3wks).

Outcomes

Primary Outcome Measures

Organ-preservation adapted DFS
The investigators use the definition of organ-preservation adopted DFS proposed in the international consensus statement for preoperative treatment (75). It is defined as the period from the date of allocation to the earliest of the following events. Surgery difficult due to local progression or study subject unfit for surgery R2 resection of primary tumor ( not including Circumferential resection margin (CRM) positive ) Local recurrence after R0/1 resection of primary tumor Local regrowth for which Salvage surgery is not possible during NOM Appearance of distant metastases Occurrence of second primary colorectal cancer Development of second primary other cancers Death (treatment-related death, death from the same cancer, death from a different type of cancer, non-cancer-related death)

Secondary Outcome Measures

cCR rate
The investigators will use the Memorial Sloan Kettering Regression Schema, which is the cCR standard for TNT clinical trials conducted mainly in the United States. For judgment, a gastrointestinal endoscopist, a pathological diagnostician, and a gastrointestinal surgeon discuss and comprehensively judge.
Clinical response (cCR+near CR [nCR]) rate
The investigators will use the Memorial Sloan Kettering Regression Schema, which is the cCR standard for TNT clinical trials conducted mainly in the United States. For judgment, a gastrointestinal endoscopist, a pathological diagnostician, and a gastrointestinal surgeon discuss and comprehensively judge.
Proportion of NOM selection
The proportion of the number of research subjects for whom NOM was selected at the time of re-evaluation to the analysis population as the numerator. Study subjects who died of any cause before the re-evaluation decision date will be treated as "no complete resection" and included in the denominator but not the numerator.
Recurrence type and recurrence rate
The recurrence site is classified into local recurrence, distant recurrence, and unknown, and is defined as "recurrence type". Select multiple categories if recurrence is observed at multiple sites at the time of the first recurrence.
Distant metastases free survival (DMFS)
The period from the date of allocation to the date of determination of distant metastasis or the date of death due to any cause, whichever is earlier. An event that corresponds to any of the following is defined as a DMFS event. Distant metastasis Death (treatment-related death, death from the same cancer, death from a different type of cancer, non-cancer-related death)
Local recurrence-free survival (LRFS)
The period from the date of allocation to the date of local recurrence or the date of death due to any cause, whichever is earlier. An event that corresponds to any of the following is defined as an LRFS event. Local recurrence Death (treatment-related death, death from the same cancer, death from a different type of cancer, non-cancer-related death)
Overall survival (OS)
From the date of allocation to the date of death due to any cause. Based on " Protocol 8.2.17 Confirmation of outcome and confirmation of recurrence after protocol treatment", the confirmation of survival should be recorded in the medical record, etc.). Patients with no follow-up will be censored on the date of final confirmation of survival.
TME-free survival
As the earliest of the date of definitive TME at reevaluation, the date of TME at local recurrence (excluding local excision), and the date of death from any cause. An event corresponding to any of the following is defined as a TME free survival event. TME when electing surgery at reevaluation TME with salvageable local regrowth in NOM Death (treatment-related death, death from the same cancer, death from a different type of cancer, non-cancer-related death)
TME-free DFS
With the date of assignment as the starting date, the date on which radical TME was performed at reevaluation, the date on which TME was performed at the time of local recurrence (excluding local excision), and Organ-preservation adopted DFS defined in Protocol 12.2.1. The period up to the earliest of the event occurrence dates. An event that corresponds to any of the following is defined as an event of TME-free disease-free survival. TME when electing surgery at reevaluation TME with salvageable local regrowth in NOM Organ preservation - adopted DFS defined in Protocol 12.2.1. is not applicable because TME is implemented)
Protocol treatment completion rate
The analysis population who completed protocol treatment.
Relative dose intensity (RDI)
RDI is calculated for each case, each cycle, and each drug (capecitabine, oxaliplatin, irinotecan) in the analysis target population. The actual number of cycle days refers to the number of days from the start of the corresponding course to the start date of the next course, but the actual number of cycle days in the final course is the number of days from the start date of the last course to the actual day of administration of capecitabine + 6 days. defined as RDI (%) = (Actual Dose/Prescribed Dose) x (21/Actual Cycle Days) x 100
QOL assessment (LARS score, EORTC QLQ-C30, and SF-36)
Using a quality of life questionnaire to assess the following items: LARS score, EORTC QLQ-C30, SF-36
Incidence of preoperative treatment-related adverse events
Incidence of preoperative treatment-related adverse events determined by CTCAE ver5.0
Pathological complete response (pCR) rate in the surgical subgroup
Pathological response evaluation will be performed on the surgical specimens of the subgroup that underwent surgical resection in the protocol treatment. Histopathological evaluation of antitumor efficacy is based on the American Joint Committee on Cancer (AJCC) evaluation method. pCR is defined as no viable tumor cells not only in the primary tumor but also in the regional lymph nodes (ypT0N0). Percentage of study subjects judged to be pCR in the analysis population.
Radical resection rate in the surgical subgroup
Proportion of study participants who underwent a complete resection (confirmed postoperative pathological R0) in the analyzed population in the surgical resection subgroup in protocol treatment. Study subjects who died of any cause prior to the date of surgery were treated as "no complete resection" and included in the denominator but not the numerator.
Local recurrence-free survival (LRFS) in the surgical subgroup
In the subgroup that underwent surgical resection in protocol treatment, the period from the date of surgery to the date of local recurrence or the date of death from any cause, whichever comes first.
Surgery-related adverse event rate determined by Clavien-Dindo classification v2.0 in the surgical subgroup
For early (within 30 days) and late (31-90 days) postoperative adverse events after the end of surgical therapy, the worst grade according to the Clavien-Dindo classification v2.0 is calculated.
Local re-enlargement rate in the NOM subgroup
Proportion of study subjects with local regrowth in the analysis population in the subgroups that underwent NOM.
Time for local regrowth in the NOM subgroup
In the subgroup that underwent NOM, the date of NOM determination is the starting date, and the period from the date of local regrowth to the date of death from any cause, whichever is earlier.
Proportion of salvage surgery in local re-enlargement cases in the NOM subgroup
In the NOM subgroup, the proportion of study subjects with local regrowth and salvage surgery in the analysis population.
Time until salvage surgery in the NOM subgroup
In the NOM subgroup, the time to the date of salvage surgery at the time of local regrowth or the date of death from any cause, whichever is earliest.
Surgery-related adverse event rate determined by Clavien-Dindo classification v2.0 in salvage surgery cases in the NOM subgroup
In the subgroup that underwent NOM, among the population to be analyzed, in cases where local regrowth was performed and salvage surgery was performed, early (within 30 days) and late (31-90 days) postoperative adverse events after the end of surgical therapy , find the worst grade by Clavien-Dindo classification v2.0.
Proportion of radical resection in salvage surgery cases in the NOM subgroup
Proportion of study subjects with local regrowth and radical salvage surgery in the analyzed population in the NOM subgroup.

Full Information

First Posted
December 1, 2022
Last Updated
May 28, 2023
Sponsor
National Cancer Center Hospital East
Collaborators
Japan Agency for Medical Research and Development
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1. Study Identification

Unique Protocol Identification Number
NCT05646511
Brief Title
Total Neoadjuvant Therapy of SCRT+CAPOX vs SCRT+CAPOXIRI for Locally Advanced Rectal Cancer (ENSEMBLE)
Acronym
ENSEMBLE
Official Title
A Multicenter Randomized Phase III Study of Short-term Radiotherapy Plus CAPOX and Short-term Radiotherapy Plus CAPOXIRI as Preoperative Treatment for Locally Advanced Rectal Cancer
Study Type
Interventional

2. Study Status

Record Verification Date
May 2023
Overall Recruitment Status
Recruiting
Study Start Date
November 21, 2022 (Actual)
Primary Completion Date
December 31, 2029 (Anticipated)
Study Completion Date
December 31, 2030 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
National Cancer Center Hospital East
Collaborators
Japan Agency for Medical Research and Development

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This trial is a multicenter randomized Phase III study to verify the superiority of short-course preoperative radiation (SCRT) and CAPOXIRI over SCRT and CAPOX as preoperative treatments for locally advanced rectal cancer.
Detailed Description
Total neoadjuvant therapy (TNT) for locally advanced rectal cancer (LARC) has the promise, which means non-operative management (NOM) enable more patients (pts) with a complete clinical response (cCR) or near-complete clinical responses (nCR) after TNT to avoid subsequent radical surgery, with potentially maintaining anorectal function and quality of life (QoL). Recently, PRODIGE-23 trial demonstrated that triplet regimen (Irinotecan, oxaliplatin and fluoropyrimidine) before preoperative chemoradiotherapy (CRT) significantly improved outcomes compared with CRT. However, there has been no prospective study comparing consolidation triplet with doublet regimens following short course radiotherapy (SCRT). The aim of this randomized phase III trial is to test superiority of consolidation irinotecan, capecitabine and oxaliplatin (CAPOXIRI) vs. capecitabine and oxaliplatin (CAPOX) following SCRT as TNT in pts with LARC. Pts in both groups will be re-staged after completing TNT before radical surgery according to the Memorial Sloan Kettering Regression Schema; pts with incomplete response (iCR) will undergo total mesorectal excision (TME), cCR pts will receive NOM, and nCR pts will undergo TME or NOM by a physician discretion under the recommendation of blind assessment by the designated NOM central committee. Pts will be followed by CT, MRI, colonoscopy and liquid biopsy every 4 months for 2 years, and every 6 months thereafter up to 5 years. To detect a decrease in 3-year cumulative probability of organ preservation-adapted Disease free survival (DFS) from 75.0% to 81.7%, corresponding to a target hazard ratio of 0·70, a total of 608 pts (196 events) would achieve 70% power at a two-sided α significance level of 0.05.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Locally Advanced Rectal Cancer
Keywords
Radiation, CAPOXIRI, CAPOX, Rectal cancer, Total neoadjuvant therapy, Rectal Neoplasms, Colorectal Neoplasms, Intestinal Neoplasms, Gastrointestinal Neoplasms, Digestive System Neoplasms, Capecitabine, Oxaliplatin, Irinotecan, Antineoplastic Agents, Chemotherapy, Non-operative management, Surgery, MRI, Restaging, QOL, Organ preservation

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Model Description
standard arm: 5x5Gy -> 12 wks CAPOX -> restating -> surgery or non-operative management experimental arm: 5x5Gy -> 12 wks CAPOXIRI -> restating -> surgery or non-operative management
Masking
None (Open Label)
Allocation
Randomized
Enrollment
608 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Control arm SCRT+CAPOX
Arm Type
Active Comparator
Arm Description
The standard-of-care group receives short-course radiation therapy (5 × 5 Gy) followed by six cycles of CAPOX (capecitabine 1000 mg/m2 orally twice daily on days 1-14, oxaliplatin 130 mg/m2 intravenously on day 1, q3wks).
Arm Title
Experimental arm SCRT+CAPOXIRI
Arm Type
Experimental
Arm Description
The standard-of-care group receives short-course radiation therapy (5 × 5 Gy) followed by six cycles of CAPOX (capecitabine 1000 mg/m2 orally twice daily on days 1-14, oxaliplatin 130 mg/m2 intravenously on day 1, q3wks).
Intervention Type
Radiation
Intervention Name(s)
SCRT
Other Intervention Name(s)
Active Comparator & Experimental
Intervention Description
5x5 Gy: 25 Gy
Intervention Type
Drug
Intervention Name(s)
CAPOX
Other Intervention Name(s)
Active Comparator
Intervention Description
Six cycles of CAPOX capecitabine 1000 mg/m2 orally twice daily on days 1-14, oxaliplatin 130 mg/m2 intravenously on day 1, every 3 weeks
Intervention Type
Drug
Intervention Name(s)
CAPOXIRI
Other Intervention Name(s)
Experimental
Intervention Description
Six cycles of CAPOX capecitabine 800 mg/m2 orally twice daily on days 1-14, oxaliplatin 130 mg/m2 intravenously on day 1 and irinotecan 200 mg/m2 intravenously on day 1, every 3 weeks)
Primary Outcome Measure Information:
Title
Organ-preservation adapted DFS
Description
The investigators use the definition of organ-preservation adopted DFS proposed in the international consensus statement for preoperative treatment (75). It is defined as the period from the date of allocation to the earliest of the following events. Surgery difficult due to local progression or study subject unfit for surgery R2 resection of primary tumor ( not including Circumferential resection margin (CRM) positive ) Local recurrence after R0/1 resection of primary tumor Local regrowth for which Salvage surgery is not possible during NOM Appearance of distant metastases Occurrence of second primary colorectal cancer Development of second primary other cancers Death (treatment-related death, death from the same cancer, death from a different type of cancer, non-cancer-related death)
Time Frame
Up to 3 years. It is defined as the period from the allocation date to the earliest of the following events.
Secondary Outcome Measure Information:
Title
cCR rate
Description
The investigators will use the Memorial Sloan Kettering Regression Schema, which is the cCR standard for TNT clinical trials conducted mainly in the United States. For judgment, a gastrointestinal endoscopist, a pathological diagnostician, and a gastrointestinal surgeon discuss and comprehensively judge.
Time Frame
1-3 weeks (Days 7-21) from the completion of preoperative chemotherapy or the date of discontinuation.
Title
Clinical response (cCR+near CR [nCR]) rate
Description
The investigators will use the Memorial Sloan Kettering Regression Schema, which is the cCR standard for TNT clinical trials conducted mainly in the United States. For judgment, a gastrointestinal endoscopist, a pathological diagnostician, and a gastrointestinal surgeon discuss and comprehensively judge.
Time Frame
Within 1-3 weeks (Days 7-21) from the completion of preoperative chemotherapy or the date of discontinuation.
Title
Proportion of NOM selection
Description
The proportion of the number of research subjects for whom NOM was selected at the time of re-evaluation to the analysis population as the numerator. Study subjects who died of any cause before the re-evaluation decision date will be treated as "no complete resection" and included in the denominator but not the numerator.
Time Frame
3-6 weeks (Days 21-42) from the completion of preoperative chemotherapy or the date of discontinuation.
Title
Recurrence type and recurrence rate
Description
The recurrence site is classified into local recurrence, distant recurrence, and unknown, and is defined as "recurrence type". Select multiple categories if recurrence is observed at multiple sites at the time of the first recurrence.
Time Frame
3 years (up to 5 years)
Title
Distant metastases free survival (DMFS)
Description
The period from the date of allocation to the date of determination of distant metastasis or the date of death due to any cause, whichever is earlier. An event that corresponds to any of the following is defined as a DMFS event. Distant metastasis Death (treatment-related death, death from the same cancer, death from a different type of cancer, non-cancer-related death)
Time Frame
3 years (up to 5 years)
Title
Local recurrence-free survival (LRFS)
Description
The period from the date of allocation to the date of local recurrence or the date of death due to any cause, whichever is earlier. An event that corresponds to any of the following is defined as an LRFS event. Local recurrence Death (treatment-related death, death from the same cancer, death from a different type of cancer, non-cancer-related death)
Time Frame
3 years (up to 5 years)
Title
Overall survival (OS)
Description
From the date of allocation to the date of death due to any cause. Based on " Protocol 8.2.17 Confirmation of outcome and confirmation of recurrence after protocol treatment", the confirmation of survival should be recorded in the medical record, etc.). Patients with no follow-up will be censored on the date of final confirmation of survival.
Time Frame
3 years (up to 5 years)
Title
TME-free survival
Description
As the earliest of the date of definitive TME at reevaluation, the date of TME at local recurrence (excluding local excision), and the date of death from any cause. An event corresponding to any of the following is defined as a TME free survival event. TME when electing surgery at reevaluation TME with salvageable local regrowth in NOM Death (treatment-related death, death from the same cancer, death from a different type of cancer, non-cancer-related death)
Time Frame
3 years (up to 5 years)
Title
TME-free DFS
Description
With the date of assignment as the starting date, the date on which radical TME was performed at reevaluation, the date on which TME was performed at the time of local recurrence (excluding local excision), and Organ-preservation adopted DFS defined in Protocol 12.2.1. The period up to the earliest of the event occurrence dates. An event that corresponds to any of the following is defined as an event of TME-free disease-free survival. TME when electing surgery at reevaluation TME with salvageable local regrowth in NOM Organ preservation - adopted DFS defined in Protocol 12.2.1. is not applicable because TME is implemented)
Time Frame
3 years (up to 5 years)
Title
Protocol treatment completion rate
Description
The analysis population who completed protocol treatment.
Time Frame
Immediately after the completion of preoperative chemotherapy or the date of discontinuation.
Title
Relative dose intensity (RDI)
Description
RDI is calculated for each case, each cycle, and each drug (capecitabine, oxaliplatin, irinotecan) in the analysis target population. The actual number of cycle days refers to the number of days from the start of the corresponding course to the start date of the next course, but the actual number of cycle days in the final course is the number of days from the start date of the last course to the actual day of administration of capecitabine + 6 days. defined as RDI (%) = (Actual Dose/Prescribed Dose) x (21/Actual Cycle Days) x 100
Time Frame
Immediately after the completion of preoperative chemotherapy or the date of discontinuation.
Title
QOL assessment (LARS score, EORTC QLQ-C30, and SF-36)
Description
Using a quality of life questionnaire to assess the following items: LARS score, EORTC QLQ-C30, SF-36
Time Frame
3 years
Title
Incidence of preoperative treatment-related adverse events
Description
Incidence of preoperative treatment-related adverse events determined by CTCAE ver5.0
Time Frame
Immediately after the completion of preoperative chemotherapy or the date of discontinuation.
Title
Pathological complete response (pCR) rate in the surgical subgroup
Description
Pathological response evaluation will be performed on the surgical specimens of the subgroup that underwent surgical resection in the protocol treatment. Histopathological evaluation of antitumor efficacy is based on the American Joint Committee on Cancer (AJCC) evaluation method. pCR is defined as no viable tumor cells not only in the primary tumor but also in the regional lymph nodes (ypT0N0). Percentage of study subjects judged to be pCR in the analysis population.
Time Frame
Immediately after the evaluation of the histopathological findings after surgery
Title
Radical resection rate in the surgical subgroup
Description
Proportion of study participants who underwent a complete resection (confirmed postoperative pathological R0) in the analyzed population in the surgical resection subgroup in protocol treatment. Study subjects who died of any cause prior to the date of surgery were treated as "no complete resection" and included in the denominator but not the numerator.
Time Frame
3 years (up to 5 years)
Title
Local recurrence-free survival (LRFS) in the surgical subgroup
Description
In the subgroup that underwent surgical resection in protocol treatment, the period from the date of surgery to the date of local recurrence or the date of death from any cause, whichever comes first.
Time Frame
3 years (up to 5 years)
Title
Surgery-related adverse event rate determined by Clavien-Dindo classification v2.0 in the surgical subgroup
Description
For early (within 30 days) and late (31-90 days) postoperative adverse events after the end of surgical therapy, the worst grade according to the Clavien-Dindo classification v2.0 is calculated.
Time Frame
For early (within 30 days) and late (31-90 days) postoperative adverse events after the end of surgical therapy
Title
Local re-enlargement rate in the NOM subgroup
Description
Proportion of study subjects with local regrowth in the analysis population in the subgroups that underwent NOM.
Time Frame
3 years (up to 5 years)
Title
Time for local regrowth in the NOM subgroup
Description
In the subgroup that underwent NOM, the date of NOM determination is the starting date, and the period from the date of local regrowth to the date of death from any cause, whichever is earlier.
Time Frame
3 years (up to 5 years)
Title
Proportion of salvage surgery in local re-enlargement cases in the NOM subgroup
Description
In the NOM subgroup, the proportion of study subjects with local regrowth and salvage surgery in the analysis population.
Time Frame
3 years (up to 5 years)
Title
Time until salvage surgery in the NOM subgroup
Description
In the NOM subgroup, the time to the date of salvage surgery at the time of local regrowth or the date of death from any cause, whichever is earliest.
Time Frame
3 years (up to 5 years)
Title
Surgery-related adverse event rate determined by Clavien-Dindo classification v2.0 in salvage surgery cases in the NOM subgroup
Description
In the subgroup that underwent NOM, among the population to be analyzed, in cases where local regrowth was performed and salvage surgery was performed, early (within 30 days) and late (31-90 days) postoperative adverse events after the end of surgical therapy , find the worst grade by Clavien-Dindo classification v2.0.
Time Frame
For early (within 30 days) and late (31-90 days) postoperative adverse events after the end of surgical therapy
Title
Proportion of radical resection in salvage surgery cases in the NOM subgroup
Description
Proportion of study subjects with local regrowth and radical salvage surgery in the analyzed population in the NOM subgroup.
Time Frame
3 years (up to 5 years)
Other Pre-specified Outcome Measures:
Title
liquid biopsy
Description
Analysis using liquid biopsy will be performed to identify biomarkers that predict therapeutic effects by performing blood genome profiling.
Time Frame
3 years (up to 5 years)
Title
Artificial Intelligence (AI) (deep learning) analysis
Description
Using multiple algorithms, in addition to colonoscopy and pelvic MRI images at each point, clinicopathological features, various biomarkers, and QOL will be utilized to estimate the optimal treatment method for individual research subjects
Time Frame
3 years (up to 5 years)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: The content of this research was fully explained, and written informed consent was obtained from the subject. Histologically confirmed rectal adenocarcinoma. Radical resection is clinically possible without any distant metastases on imaging studies. Age of 18 years or older on the date of consent acquisition. Eastern Cooperative Oncology Group (ECOG) PS 0-1 (PS 0 if aged 70 years or older on consent acquisition date). Inferior margin of the tumor is within 12 cm of the AV. No prior tumor treatment. No history of radiation therapy to the pelvis, including treatment for other cancer types. Cases with cT3-4N0M0*or T1-4N1-2M0 based on Union Internationale Contre le Cancer (UICC) 8th edition. (*5 cm< AV ≤ 10 cm, T3a/bN0M0, extramural venous invasion (EMVI) -, mesorectal fascia (MRF) clear and 10 cm < AV ≤ 12 cm, T3a/bN0-1M0, EMVI-, MRF clear are eligible only for those who refused surgery) UGT1A1 is wild-type or single heterozygous. Criteria for major organ function within 28 days prior to enrollment. If there are multiple test results within this period, the most recent one will be used, and blood transfusions and hematopoietic factor preparations will not be administered within 14 days before the test date for measurements before registration. Neutrophil count: ≥1,500/mm3 Platelet count: ≥10.0×10 4/mm3 Hemoglobin concentration: ≥9.0 g/dL Total bilirubin: ≤2.0 mg/dL Aspartate transaminase (AST): ≤100 IU/L or less Alanine transaminase (ALT): ≤100 IU/L or less Serum creatinine: Creatinine clearance ≥30 mL/min (by Cockcroft & Gault formula) Exclusion Criteria: Extensive surgery (excluding colostomy and central venous port construction) within 4 weeks before starting protocol treatment. Complications or history of severe lung disease (such as interstitial pneumonia, pulmonary fibrosis, and severe emphysema). Colonic stent in place. Contraindications for MRI such as cardiac pacemakers. Serious comorbidities (such as heart failure, renal failure, liver failure, intestinal paralysis, intestinal obstruction, uncontrolled diabetes, and active inflammatory bowel disease). Patients with multiple active cancers (simultaneous multiple cancers or metachronous multiple cancers with a disease-free interval of 5 years or less). However, carcinoma in situ or lesions equivalent to intramucosal carcinoma, which can be cured by local treatment, are not treated as active multiple cancers. Pregnant women, lactating women, positive pregnancy test, or unwillingness to use contraception. Hepatitis B surface (HBs) antigen positive or hepatitis C virus (HCV) antibody-positive. However, HCV-RNA-negative can be registered. Have human immunodeficiency virus (HIV) infection. MSI-high (MSI-H) or defective mismatch repair (dMMR) is known. Unwilling to donate specimens for "Research on gene profiling and clinical significance using clinical specimens from cancer patients" for whole-genome analysis based on the "Action Plan for Whole-Genome Analysis, etc." (CONDUCTOR study). Any other patients the principal investigator or co-investigator deems inappropriate for study participation.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Yoshinori Kagawa, MD., PhD
Phone
+81-6-6692-1201
Email
yoshikagawa@gh.opho.jp
First Name & Middle Initial & Last Name or Official Title & Degree
Jun Watanabe, MD., PhD
Phone
+81-45-261-5656
Email
jun0926@yokohama-cu.ac.jp
Facility Information:
Facility Name
National Cancer Center Hospital East
City
Chiba
Country
Japan
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Takayuki Yoshino, Dr.
Phone
+81-4-7133-1111
Facility Name
Kyushu University Hospital
City
Fukuoka
Country
Japan
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Eiji Oki, Dr.
Phone
+81-92-641-1151
Facility Name
National Hospital Organization Kyushu Cancer Center
City
Fukuoka
Country
Japan
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Masahiko Sugiyama, Dr.
Phone
+81-92-557-6100
Facility Name
National Hospital Organization Kyushu Medical Center
City
Fukuoka
Country
Japan
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Tetsuya Kusumoto, Dr.
Phone
+81-92-852-0700
Facility Name
Gifu University Hospital
City
Gifu
Country
Japan
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Nobuhisa Matsuhashi, Dr.
Phone
+81-58-230-6000
Facility Name
Hirosaki University Hospital
City
Hirosaki
Country
Japan
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Miura Takuya, Dr.
Phone
+81-172-36-2111
Facility Name
Hiroshima University Hospital
City
Hiroshima
Country
Japan
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Hideki Ohdan, Dr.
Phone
+81-82-257-5555
Facility Name
St. Marianna University Hospital
City
Kawasaki
Country
Japan
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Naoki Izawa, Dr.
Phone
+81-44-977-8111
Facility Name
University of Occupational and Environmental Health Hospital
City
Kitakyushu
Country
Japan
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Keiji Hirata, Dr.
Phone
+81-93-603-1611
Facility Name
Nagoya University Hospital
City
Nagoya
Country
Japan
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Goro Nakayama, Dr.
Phone
+81-52-741-2111
Facility Name
Ohara Memorial Kurashiki Central Medical Organization Kurashiki Central Hospital
City
Okayama
Country
Japan
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Mitsuru Yokota, Dr.
Phone
+81-86-422-0210
Facility Name
Kindai University Hospital
City
Osaka
Country
Japan
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Junichiro Kawamura, Dr.
Phone
+81-72-366-0221
Facility Name
National Hospital Organization Osaka Medical Center
City
Osaka
Country
Japan
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Takesh Kato, Dr.
Phone
+81-6-6942-1331
Facility Name
Osaka Prefectural Hospital Organization Osaka Acute and General Medical Center
City
Osaka
Country
Japan
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Yoshinori Kagawa, Dr.
Phone
+81-6-6692-1201
Facility Name
Osaka University Hospital
City
Osaka
Country
Japan
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Mamoru Uemura, Dr.
Phone
+81-6-6879-5111
Facility Name
Kitasato University Hospital
City
Sagamihara
Country
Japan
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Takeshi Naito, Dr.
Phone
+81-42-778-8111
Facility Name
Sapporo Medical University Hospital
City
Sapporo
Country
Japan
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Ichiro Takemasa, Dr.
Phone
+81-11-611-2111
Facility Name
Foundation for Cancer Research Ariake Hospital
City
Tokyo
Country
Japan
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Takashi Akiyoshi, Dr.
Phone
+81-3-3520-0111
Facility Name
Keio University Hospital
City
Tokyo
Country
Japan
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Takeshi Okabayashi, Dr.
Phone
+81-3-3353-1211
Facility Name
National Cancer Center Hospital
City
Tokyo
Country
Japan
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Yukihide Kanemitsu, Dr.
Phone
+81-3-3542-2511
Facility Name
Nippon Medical School Hospital
City
Tokyo
Country
Japan
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Takeshi Yamada, Dr.
Phone
+81-3-3822-2131
Facility Name
Tokyo Metropolitan Hospital Organization Tokyo Metropolitan Komagome Hospital
City
Tokyo
Country
Japan
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Kazushige Kawai, Dr.
Phone
+81-3-3823-2101
Facility Name
Kanagawa Prefectural Hospital Organization Kanagawa Cancer Center
City
Yokohama
Country
Japan
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Manabu Shiozawa, Dr.
Phone
+81-45-520-2222
Facility Name
Yokohama City University Hospital
City
Yokohama
Country
Japan
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Atsushi Ishibe, Dr.
Phone
+81-45-787-2800
Facility Name
Yokohama City University Medical Center
City
Yokohama
Country
Japan
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jun Watanabe, Dr.
Phone
+81-45-261-5656
Facility Name
Federation of National Public Service Personnel Mutual Aid Associations Yokosuka Mutual Aid Hospital
City
Yokosuka
Country
Japan
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Hirokazu Suwa, Dr.
Phone
+81-46-822-2710

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
A part of the omics analysis data obtained in the analysis of this study may be disclosed through public databases such as the "Human Database" operated by National Bioscience Database Center (NBDC) in Japan Science and Technology Agency (JST). When registering data, re-anonymization will be provided to strengthen the protections of personal information. At the time of NBDC registration, we will comply with the "NBDC Guidelines for Human Data Sharing" and "NBDC Security Guidelines for Human Data(for Data Providers)" .

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Total Neoadjuvant Therapy of SCRT+CAPOX vs SCRT+CAPOXIRI for Locally Advanced Rectal Cancer (ENSEMBLE)

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