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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Locally Advanced Rectal Cancer
• Intervention / Treatment: Radiation: SCRT; Drug: CAPOX; Drug: CAPOXIRI

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.

• Study Type: Interventional
• Enrollment (Estimated): 608
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Yoshinori Kagawa, MD., PhD; Phone Number: +81-6-6692-1201; Email: yoshikagawa@gh.opho.jp
• Study Contact Backup: Name: Jun Watanabe, MD., PhD; Phone Number: +81-45-261-5656; Email: jun0926@yokohama-cu.ac.jp

Study Locations

• Japan
  • Chiba, Japan
    • Recruiting
    • National Cancer Center Hospital East
    • Contact: Takayuki Yoshino, Dr.; Phone Number: +81-4-7133-1111
  • Fukuoka, Japan
    • Recruiting
    • National Hospital Organization Kyushu Cancer Center
    • Contact: Masahiko Sugiyama, Dr.; Phone Number: +81-92-557-6100
  • Fukuoka, Japan
    • Recruiting
    • Kyushu University Hospital
    • Contact: Eiji Oki, Dr.; Phone Number: +81-92-641-1151
  • Fukuoka, Japan
    • Recruiting
    • National Hospital Organization Kyushu Medical Center
    • Contact: Tetsuya Kusumoto, Dr.; Phone Number: +81-92-852-0700
  • Gifu, Japan
    • Recruiting
    • Gifu University Hospital
    • Contact: Nobuhisa Matsuhashi, Dr.; Phone Number: +81-58-230-6000
  • Hirosaki, Japan
    • Recruiting
    • Hirosaki University Hospital
    • Contact: Miura Takuya, Dr.; Phone Number: +81-172-36-2111
  • Hiroshima, Japan
    • Recruiting
    • Hiroshima University Hospital
    • Contact: Hideki Ohdan, Dr.; Phone Number: +81-82-257-5555
  • Kawasaki, Japan
    • Recruiting
    • St. Marianna University Hospital
    • Contact: Naoki Izawa, Dr.; Phone Number: +81-44-977-8111
  • Kitakyushu, Japan
    • Recruiting
    • University of Occupational and Environmental Health Hospital
    • Contact: Keiji Hirata, Dr.; Phone Number: +81-93-603-1611
  • Nagoya, Japan
    • Recruiting
    • Nagoya University Hospital
    • Contact: Goro Nakayama, Dr.; Phone Number: +81-52-741-2111
  • Okayama, Japan
    • Recruiting
    • Ohara Memorial Kurashiki Central Medical Organization Kurashiki Central Hospital
    • Contact: Mitsuru Yokota, Dr.; Phone Number: +81-86-422-0210
  • Osaka, Japan
    • Recruiting
    • Kindai University Hospital
    • Contact: Junichiro Kawamura, Dr.; Phone Number: +81-72-366-0221
  • Osaka, Japan
    • Recruiting
    • National Hospital Organization Osaka Medical Center
    • Contact: Takesh Kato, Dr.; Phone Number: +81-6-6942-1331
  • Osaka, Japan
    • Recruiting
    • Osaka Prefectural Hospital Organization Osaka Acute and General Medical Center
    • Contact: Yoshinori Kagawa, Dr.; Phone Number: +81-6-6692-1201
  • Osaka, Japan
    • Recruiting
    • Osaka University Hospital
    • Contact: Mamoru Uemura, Dr.; Phone Number: +81-6-6879-5111
  • Sagamihara, Japan
    • Recruiting
    • Kitasato University Hospital
    • Contact: Takeshi Naito, Dr.; Phone Number: +81-42-778-8111
  • Sapporo, Japan
    • Recruiting
    • Sapporo Medical University Hospital
    • Contact: Ichiro Takemasa, Dr.; Phone Number: +81-11-611-2111
  • Tokyo, Japan
    • Recruiting
    • National Cancer Center Hospital
    • Contact: Yukihide Kanemitsu, Dr.; Phone Number: +81-3-3542-2511
  • Tokyo, Japan
    • Recruiting
    • Keio University Hospital
    • Contact: Takeshi Okabayashi, Dr.; Phone Number: +81-3-3353-1211
  • Tokyo, Japan
    • Recruiting
    • Foundation for Cancer Research Ariake Hospital
    • Contact: Takashi Akiyoshi, Dr.; Phone Number: +81-3-3520-0111
  • Tokyo, Japan
    • Recruiting
    • Nippon Medical School Hospital
    • Contact: Takeshi Yamada, Dr.; Phone Number: +81-3-3822-2131
  • Tokyo, Japan
    • Recruiting
    • Tokyo Metropolitan Hospital Organization Tokyo Metropolitan Komagome Hospital
    • Contact: Kazushige Kawai, Dr.; Phone Number: +81-3-3823-2101
  • Yokohama, Japan
    • Recruiting
    • Kanagawa Prefectural Hospital Organization Kanagawa Cancer Center
    • Contact: Manabu Shiozawa, Dr.; Phone Number: +81-45-520-2222
  • Yokohama, Japan
    • Recruiting
    • Yokohama City University Hospital
    • Contact: Atsushi Ishibe, Dr.; Phone Number: +81-45-787-2800
  • Yokohama, Japan
    • Recruiting
    • Yokohama City University Medical Center
    • Contact: Jun Watanabe, Dr.; Phone Number: +81-45-261-5656
  • Yokosuka, Japan
    • Recruiting
    • Federation of National Public Service Personnel Mutual Aid Associations Yokosuka Mutual Aid Hospital
    • Contact: Hirokazu Suwa, Dr.; Phone Number: +81-46-822-2710

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. The content of this research was fully explained, and written informed consent was obtained from the subject.
2. Histologically confirmed rectal adenocarcinoma.
3. Radical resection is clinically possible without any distant metastases on imaging studies.
4. Age of 18 years or older on the date of consent acquisition.
5. Eastern Cooperative Oncology Group (ECOG) PS 0-1 (PS 0 if aged 70 years or older on consent acquisition date).
6. Inferior margin of the tumor is within 12 cm of the AV.
7. No prior tumor treatment.
8. No history of radiation therapy to the pelvis, including treatment for other cancer types.

9. 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)

10. UGT1A1 is wild-type or single heterozygous.

11. 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.

    1. Neutrophil count: ≥1,500/mm3
    2. Platelet count: ≥10.0×10 4/mm3
    3. Hemoglobin concentration: ≥9.0 g/dL
    4. Total bilirubin: ≤2.0 mg/dL
    5. Aspartate transaminase (AST): ≤100 IU/L or less
    6. Alanine transaminase (ALT): ≤100 IU/L or less
    7. Serum creatinine: Creatinine clearance ≥30 mL/min (by Cockcroft & Gault formula)

Exclusion Criteria:

1. Extensive surgery (excluding colostomy and central venous port construction) within 4 weeks before starting protocol treatment.
2. Complications or history of severe lung disease (such as interstitial pneumonia, pulmonary fibrosis, and severe emphysema).
3. Colonic stent in place.
4. Contraindications for MRI such as cardiac pacemakers.
5. Serious comorbidities (such as heart failure, renal failure, liver failure, intestinal paralysis, intestinal obstruction, uncontrolled diabetes, and active inflammatory bowel disease).
6. 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.
7. Pregnant women, lactating women, positive pregnancy test, or unwillingness to use contraception.
8. Hepatitis B surface (HBs) antigen positive or hepatitis C virus (HCV) antibody-positive. However, HCV-RNA-negative can be registered.
9. Have human immunodeficiency virus (HIV) infection.
10. MSI-high (MSI-H) or defective mismatch repair (dMMR) is known.
11. 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).
12. Any other patients the principal investigator or co-investigator deems inappropriate for study participation.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Control arm SCRT+CAPOX; 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).	Radiation: SCRT; 5x5 Gy: 25 Gy; Other Names: Active Comparator & Experimental; Drug: CAPOX; 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; Other Names: Active Comparator
Experimental: Experimental arm SCRT+CAPOXIRI; 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).	Radiation: SCRT; 5x5 Gy: 25 Gy; Other Names: Active Comparator & Experimental; Drug: CAPOXIRI; 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); Other Names: Experimental

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)	Up to 3 years. It is defined as the period from the allocation date to the earliest of the following events.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	1-3 weeks (Days 7-21) from the completion of preoperative chemotherapy or the date of discontinuation.
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.	Within 1-3 weeks (Days 7-21) from the completion of preoperative chemotherapy or the date of discontinuation.
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.	3-6 weeks (Days 21-42) from the completion of preoperative chemotherapy or the date of discontinuation.
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.	3 years (up to 5 years)
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)	3 years (up to 5 years)
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)	3 years (up to 5 years)
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.	3 years (up to 5 years)
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)	3 years (up to 5 years)
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)	3 years (up to 5 years)
Protocol treatment completion rate	The analysis population who completed protocol treatment.	Immediately after the completion of preoperative chemotherapy or the date of discontinuation.
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	Immediately after the completion of preoperative chemotherapy or the date of discontinuation.
Incidence of preoperative treatment-related adverse events	Incidence of preoperative treatment-related adverse events determined by CTCAE ver5.0	Immediately after the completion of preoperative chemotherapy or the date of discontinuation.
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.	Immediately after the evaluation of the histopathological findings after surgery
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.	3 years (up to 5 years)
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.	3 years (up to 5 years)
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.	For early (within 30 days) and late (31-90 days) postoperative adverse events after the end of surgical therapy
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.	3 years (up to 5 years)
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.	3 years (up to 5 years)
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.	3 years (up to 5 years)
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.	3 years (up to 5 years)
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.	For early (within 30 days) and late (31-90 days) postoperative adverse events after the end of surgical therapy
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.	3 years (up to 5 years)
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	3 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
liquid biopsy	Analysis using liquid biopsy will be performed to identify biomarkers that predict therapeutic effects by performing blood genome profiling.	3 years (up to 5 years)
Artificial Intelligence (AI) (deep learning) analysis	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	3 years (up to 5 years)

Collaborators and Investigators

• Sponsor: National Cancer Center Hospital East
• Collaborators: Japan Agency for Medical Research and Development

Study record dates

Study Major Dates

• Study Start (Actual): November 21, 2022
• Primary Completion (Estimated): December 31, 2029
• Study Completion (Estimated): December 31, 2030

Study Registration Dates

• First Submitted: December 1, 2022
• First Submitted That Met QC Criteria: December 9, 2022
• First Posted (Actual): December 12, 2022

Study Record Updates

• Last Update Posted (Actual): May 31, 2023
• Last Update Submitted That Met QC Criteria: May 28, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: MRI; Capecitabine; Surgery; Rectal cancer; Chemotherapy; Antineoplastic Agents; Irinotecan; Colorectal Neoplasms; Oxaliplatin; Radiation; QOL; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; CAPOX; Organ preservation; Rectal Neoplasms; Non-operative management; Total neoadjuvant therapy; CAPOXIRI; Restaging
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Rectal Neoplasms
• Other Study ID Numbers: K2022001; jRCTs031220342 (Registry Identifier: Japan Registry of Clinical Trials)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD 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)" .

Drug and device information, study documents

• 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