TNT of SCRT+CAPOX vs SCRT+CAPOXIRI for Locally Advanced Rectal Cancer
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
2 other identifiers
interventional
608
1 country
34
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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for phase_3
Started Nov 2022
Longer than P75 for phase_3
34 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
Study Start
First participant enrolled
November 21, 2022
CompletedFirst Submitted
Initial submission to the registry
December 1, 2022
CompletedFirst Posted
Study publicly available on registry
December 12, 2022
CompletedPrimary Completion
Last participant's last visit for primary outcome
December 31, 2029
ExpectedStudy Completion
Last participant's last visit for all outcomes
December 31, 2030
April 3, 2025
March 1, 2025
7.1 years
December 1, 2022
March 31, 2025
Conditions
Keywords
Outcome Measures
Primary Outcomes (1)
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. 1. Surgery difficult due to local progression or study subject unfit for surgery 2. R2 resection of primary tumor ( not including Circumferential resection margin (CRM) positive ) 3. Local recurrence after R0/1 resection of primary tumor 4. Local regrowth for which Salvage surgery is not possible during NOM 5. Appearance of distant metastases 6. Occurrence of second primary colorectal cancer 7. Development of second primary other cancers 8. 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 Outcomes (23)
cCR rate
1-3 weeks (Days 7-21) from the completion of preoperative chemotherapy or the date of discontinuation.
Clinical response (cCR+near CR [nCR]) rate
Within 1-3 weeks (Days 7-21) from the completion of preoperative chemotherapy or the date of discontinuation.
Proportion of NOM selection
3-6 weeks (Days 21-42) from the completion of preoperative chemotherapy or the date of discontinuation.
Recurrence type and recurrence rate
3 years (up to 5 years)
Distant metastases free survival (DMFS)
3 years (up to 5 years)
- +18 more secondary outcomes
Other Outcomes (2)
liquid biopsy
3 years (up to 5 years)
Artificial Intelligence (AI) (deep learning) analysis
3 years (up to 5 years)
Study Arms (2)
Control arm SCRT+CAPOX
ACTIVE COMPARATORThe 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).
Experimental arm SCRT+CAPOXIRI
EXPERIMENTALThe standard-of-care group receives short-course radiation therapy (5 × 5 Gy) followed by six cycles of CAPOXIRI (capecitabine 800 mg/m2 orally twice daily on days 1-14, oxaliplatin 130 mg/m2 intravenously on day 1, and irinotecan 150 mg/m2 intravenously on day 1\*, q3wks).
Interventions
5x5 Gy: 25 Gy
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
Six cycles of CAPOXIRI capecitabine 800 mg/m2 orally twice daily on days 1-14, oxaliplatin 130 mg/m2 intravenously on day 1 and irinotecan 150 mg/m2 intravenously on day 1, every 3 weeks
Eligibility Criteria
You may qualify if:
- 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
- +4 more criteria
You may not qualify if:
- 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.
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (34)
National Cancer Center Hospital East
Chiba, Japan
Ehime Prefectural Central Hospital
Ehime, Japan
Kyushu University Hospital
Fukuoka, Japan
National Hospital Organization Kyushu Cancer Center
Fukuoka, Japan
National Hospital Organization Kyushu Medical Center
Fukuoka, Japan
Gifu University Hospital
Gifu, Japan
Hirosaki University Hospital
Hirosaki, Japan
Hiroshima University Hospital
Hiroshima, Japan
St. Marianna University Hospital
Kawasaki, Japan
University of Occupational and Environmental Health Hospital
Kitakyushu, Japan
Kochi Medical School Hospital
Kochi, Japan
Kumamoto University Hospital
Kumamoto, Japan
Kyoto Prefectural University of Medicine
Kyoto, Japan
Nagoya University Hospital
Nagoya, Japan
Ohara Memorial Kurashiki Central Medical Organization Kurashiki Central Hospital
Okayama, Japan
Okayama University Hospital
Okayama, Japan
Kansai Medical University Hospital
Osaka, Japan
Kindai University Hospital
Osaka, Japan
National Hospital Organization Osaka Medical Center
Osaka, Japan
Osaka International Cancer Institute
Osaka, Japan
Osaka Metropolitan University Hospital
Osaka, Japan
Osaka Prefectural Hospital Organization Osaka Acute and General Medical Center
Osaka, Japan
Osaka University Hospital
Osaka, Japan
Kitasato University Hospital
Sagamihara, Japan
Sapporo Medical University Hospital
Sapporo, Japan
Keio University Hospital
Tokyo, Japan
National Cancer Center Hospital
Tokyo, Japan
Nippon Medical School Hospital
Tokyo, Japan
Tokyo Medical University Hospital
Tokyo, Japan
Tokyo Metropolitan Hospital Organization Tokyo Metropolitan Komagome Hospital
Tokyo, Japan
Kanagawa Prefectural Hospital Organization Kanagawa Cancer Center
Yokohama, Japan
Yokohama City University Hospital
Yokohama, Japan
Yokohama City University Medical Center
Yokohama, Japan
Federation of National Public Service Personnel Mutual Aid Associations Yokosuka Mutual Aid Hospital
Yokosuka, Japan
Related Publications (5)
Watanabe J, Kagawa Y, Chida K, Ando K, Kotani D, Oba K, Bando H, Hojo H, Shimamoto S, Sakashita S et al: Phase III trial of short-course radiotherapy followed by CAPOXIRI versus CAPOX in locally advanced rectal cancer: the ENSEMBLE trial. ESMO Gastrointestinal Oncology 2023, 1:9-14.
BACKGROUNDKagawa Y, Smith JJ, Fokas E, Watanabe J, Cercek A, Greten FR, Bando H, Shi Q, Garcia-Aguilar J, Romesser PB, Horvat N, Sanoff H, Hall W, Kato T, Rodel C, Dasari A, Yoshino T. Future direction of total neoadjuvant therapy for locally advanced rectal cancer. Nat Rev Gastroenterol Hepatol. 2024 Jun;21(6):444-455. doi: 10.1038/s41575-024-00900-9. Epub 2024 Mar 14.
PMID: 38485756BACKGROUNDScott AJ, Kennedy EB, Berlin J, Brown G, Chalabi M, Cho MT, Cusnir M, Dorth J, George M, Kachnic LA, Kennecke HF, Loree JM, Morris VK, Perez RO, Smith JJ, Strickland MR, Gholami S. Management of Locally Advanced Rectal Cancer: ASCO Guideline. J Clin Oncol. 2024 Oct;42(28):3355-3375. doi: 10.1200/JCO.24.01160. Epub 2024 Aug 8.
PMID: 39116386BACKGROUNDKagawa Y, Watanabe J, Uemura M, Ando K, Inoue A, Oba K, Takemasa I, Oki E. Short-term outcomes of a prospective multicenter phase II trial of total neoadjuvant therapy for locally advanced rectal cancer in Japan (ENSEMBLE-1). Ann Gastroenterol Surg. 2023 Jul 11;7(6):968-976. doi: 10.1002/ags3.12715. eCollection 2023 Nov.
PMID: 37927927BACKGROUNDKagawa Y, Ando K, Uemura M, Watanabe J, Oba K, Emi Y, Matsuhashi N, Izawa N, Muto O, Kinjo T, Takemasa I, Oki E. Phase II study of long-course chemoradiotherapy followed by consolidation chemotherapy as total neoadjuvant therapy in locally advanced rectal cancer in Japan: ENSEMBLE-2. Ann Gastroenterol Surg. 2024 Aug 3;8(6):1067-1075. doi: 10.1002/ags3.12848. eCollection 2024 Nov.
PMID: 39502728BACKGROUND
MeSH Terms
Conditions
Condition Hierarchy (Ancestors)
Central Study Contacts
Study Design
- Study Type
- interventional
- Phase
- phase 3
- Allocation
- RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- OTHER
- Responsible Party
- PRINCIPAL INVESTIGATOR
- PI Title
- MD., PhD Head of Department of Gastroenterology and Gastrointestinal Oncology
Study Record Dates
First Submitted
December 1, 2022
First Posted
December 12, 2022
Study Start
November 21, 2022
Primary Completion (Estimated)
December 31, 2029
Study Completion (Estimated)
December 31, 2030
Last Updated
April 3, 2025
Record last verified: 2025-03
Data Sharing
- IPD Sharing
- Will share
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)" .