TNT of SCRT+CAPOX vs SCRT+CAPOXIRI for Locally Advanced Rectal Cancer

NCT ID: NCT05646511

Last Updated: 2025-04-03

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

RECRUITING

Clinical Phase

PHASE3

Total Enrollment

608 participants

Study Classification

INTERVENTIONAL

Study Start Date

2022-11-21

Study Completion Date

2030-12-31

Brief Summary

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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

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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.

Conditions

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Locally Advanced Rectal Cancer

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

standard arm: 5x5Gy - - 12 wks CAPOX- - restaging - - surgery or non-operative management experimental arm: 5x5Gy - - 12 wks CAPOXIRI - - restaging - - surgery or non-operative management
Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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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).

Group Type ACTIVE_COMPARATOR

SCRT

Intervention Type RADIATION

5x5 Gy: 25 Gy

CAPOX

Intervention Type DRUG

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

Experimental arm SCRT+CAPOXIRI

The 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).

Group Type EXPERIMENTAL

SCRT

Intervention Type RADIATION

5x5 Gy: 25 Gy

CAPOXIRI

Intervention Type DRUG

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

Interventions

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SCRT

5x5 Gy: 25 Gy

Intervention Type RADIATION

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

Intervention Type DRUG

CAPOXIRI

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

Intervention Type DRUG

Other Intervention Names

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Active Comparator & Experimental Active Comparator Experimental

Eligibility Criteria

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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.
Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Japan Agency for Medical Research and Development

OTHER_GOV

Sponsor Role collaborator

National Cancer Center Hospital East

OTHER

Sponsor Role lead

Responsible Party

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Takayuki Yoshino

MD., PhD Head of Department of Gastroenterology and Gastrointestinal Oncology

Responsibility Role PRINCIPAL_INVESTIGATOR

Locations

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National Cancer Center Hospital East

Chiba, , Japan

Site Status RECRUITING

Ehime Prefectural Central Hospital

Ehime, , Japan

Site Status RECRUITING

Kyushu University Hospital

Fukuoka, , Japan

Site Status RECRUITING

National Hospital Organization Kyushu Cancer Center

Fukuoka, , Japan

Site Status RECRUITING

National Hospital Organization Kyushu Medical Center

Fukuoka, , Japan

Site Status RECRUITING

Gifu University Hospital

Gifu, , Japan

Site Status RECRUITING

Hirosaki University Hospital

Hirosaki, , Japan

Site Status RECRUITING

Hiroshima University Hospital

Hiroshima, , Japan

Site Status RECRUITING

St. Marianna University Hospital

Kawasaki, , Japan

Site Status RECRUITING

University of Occupational and Environmental Health Hospital

Kitakyushu, , Japan

Site Status RECRUITING

Kochi Medical School Hospital

Kochi, , Japan

Site Status RECRUITING

Kumamoto University Hospital

Kumamoto, , Japan

Site Status RECRUITING

Kyoto Prefectural University of Medicine

Kyoto, , Japan

Site Status RECRUITING

Nagoya University Hospital

Nagoya, , Japan

Site Status RECRUITING

Ohara Memorial Kurashiki Central Medical Organization Kurashiki Central Hospital

Okayama, , Japan

Site Status RECRUITING

Okayama University Hospital

Okayama, , Japan

Site Status RECRUITING

Kansai Medical University Hospital

Osaka, , Japan

Site Status RECRUITING

Kindai University Hospital

Osaka, , Japan

Site Status RECRUITING

National Hospital Organization Osaka Medical Center

Osaka, , Japan

Site Status RECRUITING

Osaka International Cancer Institute

Osaka, , Japan

Site Status RECRUITING

Osaka Metropolitan University Hospital

Osaka, , Japan

Site Status RECRUITING

Osaka Prefectural Hospital Organization Osaka Acute and General Medical Center

Osaka, , Japan

Site Status RECRUITING

Osaka University Hospital

Osaka, , Japan

Site Status RECRUITING

Kitasato University Hospital

Sagamihara, , Japan

Site Status RECRUITING

Sapporo Medical University Hospital

Sapporo, , Japan

Site Status RECRUITING

Keio University Hospital

Tokyo, , Japan

Site Status RECRUITING

National Cancer Center Hospital

Tokyo, , Japan

Site Status RECRUITING

Nippon Medical School Hospital

Tokyo, , Japan

Site Status RECRUITING

Tokyo Medical University Hospital

Tokyo, , Japan

Site Status RECRUITING

Tokyo Metropolitan Hospital Organization Tokyo Metropolitan Komagome Hospital

Tokyo, , Japan

Site Status RECRUITING

Kanagawa Prefectural Hospital Organization Kanagawa Cancer Center

Yokohama, , Japan

Site Status RECRUITING

Yokohama City University Hospital

Yokohama, , Japan

Site Status RECRUITING

Yokohama City University Medical Center

Yokohama, , Japan

Site Status RECRUITING

Federation of National Public Service Personnel Mutual Aid Associations Yokosuka Mutual Aid Hospital

Yokosuka, , Japan

Site Status RECRUITING

Countries

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Japan

Central Contacts

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Yoshinori Kagawa, MD., PhD

Role: CONTACT

+81-6-6945-1181

Jun Watanabe, MD., PhD

Role: CONTACT

+81-72-804-0101

Facility Contacts

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Takayuki Yoshino, Dr.

Role: primary

+81-4-7133-1111

Masanori Hotchi, Dr.

Role: primary

+81-89-947-1111

Eiji Oki, Dr.

Role: primary

+81-92-641-1151

Masahiko Sugiyama, Dr.

Role: primary

+81-92-557-6100

Tetsuya Kusumoto, Dr.

Role: primary

+81-92-852-0700

Nobuhisa Matsuhashi, Dr.

Role: primary

+81-58-230-6000

Takuya Miura, Dr.

Role: primary

+81-172-33-5111

Hideki Ohdan, Dr.

Role: primary

+81-82-257-5555

Naoki Izawa, Dr.

Role: primary

+81-44-977-8111

Keiji Hirata, Dr.

Role: primary

+81-93-603-1611

Hironaga Satake, Dr.

Role: primary

+81-88-866-5811

Yuji Miyamoto, Dr.

Role: primary

+81-96-373-5212

Tomohiro Arita, Dr.

Role: primary

+81-75-251-5111

Goro Nakayama, Dr.

Role: primary

+81-52-741-2111

Mitsuru Yokota, Dr.

Role: primary

+81-86-422-0210

Toshiyoshi Fujiwara, Dr.

Role: primary

+81-86-223-7151

Jun Watanabe, Dr.

Role: primary

+81-72-804-0101

Junichiro Kawamura, Dr.

Role: primary

+81-72-366-0221

Takeshi Kato, Dr.

Role: primary

+81-6-6942-1331

Yoshinori Kagawa, Dr.

Role: primary

+81-6-6945-1181

Kiyoshi Maeda, Dr.

Role: primary

+81-6-6645-2121

Yujiro Nishizawa, Dr.

Role: primary

+81-6-6692-1201

Mamoru Uemura, Dr.

Role: primary

+81-6-6879-5111

Takeshi Naito, Dr.

Role: primary

+81-42-778-8111

Koichi Okuya, Dr.

Role: primary

+81-11-611-2111

Koji Okabayashi, Dr.

Role: primary

+81-3-3353-1211

Yukihide Kanemitsu, Dr.

Role: primary

+81-3-3542-2511

Takeshi Yamada, Dr.

Role: primary

+81-3-3822-2131

Yuichi Nagakawa, Dr.

Role: primary

+81-3-3342-6111

Kazushige Kawai, Dr.

Role: primary

+81-3-3823-2101

Manabu Shiozawa, Dr.

Role: primary

+81-45-520-2222

Mayumi Ozawa, Dr.

Role: primary

+81-45-787-2800

Yusuke Suwa, Dr.

Role: primary

+81-45-261-5656

Hirokazu Suwa, Dr.

Role: primary

+81-46-822-2710

References

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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.

Reference Type BACKGROUND

Kagawa 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.

Reference Type BACKGROUND
PMID: 38485756 (View on PubMed)

Scott 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.

Reference Type BACKGROUND
PMID: 39116386 (View on PubMed)

Kagawa 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.

Reference Type BACKGROUND
PMID: 37927927 (View on PubMed)

Kagawa 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.

Reference Type BACKGROUND
PMID: 39502728 (View on PubMed)

Other Identifiers

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jRCTs031220342

Identifier Type: REGISTRY

Identifier Source: secondary_id

K2022001

Identifier Type: -

Identifier Source: org_study_id

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