Clinical trial NCT05646511: TNT of SCRT+CAPOX vs SCRT+CAPOXIRI for Locally Advanced Rectal Cancer
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
Overall status: RECRUITING
Phase: PHASE3
Conditions: 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
TNT
Lead sponsor: National Cancer Center Hospital East
Sponsor class: OTHER
Collaborators: name: Japan Agency for Medical Research and Development
First posted: 2022-12-12
Enrollment: 608
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 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 purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Organ-preservation adapted DFS
timeFrame: Up to 3 years. It is defined as the period from the allocation date to the earliest of the following events.
Secondary outcomes:
measure: cCR rate
timeFrame: 1-3 weeks (Days 7-21) from the completion of preoperative chemotherapy or the date of discontinuation.
measure: Clinical response (cCR+near CR [nCR]) rate
timeFrame: Within 1-3 weeks (Days 7-21) from the completion of preoperative chemotherapy or the date of discontinuation.
measure: Proportion of NOM selection
timeFrame: 3-6 weeks (Days 21-42) from the completion of preoperative chemotherapy or the date of discontinuation.
measure: Recurrence type and recurrence rate
timeFrame: 3 years (up to 5 years)
measure: Distant metastases free survival (DMFS)
timeFrame: 3 years (up to 5 years)
measure: Local recurrence-free survival (LRFS)
timeFrame: 3 years (up to 5 years)
measure: Overall survival (OS)
timeFrame: 3 years (up to 5 years)
measure: TME-free survival
timeFrame: 3 years (up to 5 years)
measure: TME-free DFS
timeFrame: 3 years (up to 5 years)
measure: Protocol treatment completion rate
timeFrame: Immediately after the completion of preoperative chemotherapy or the date of discontinuation.
measure: Relative dose intensity (RDI)
timeFrame: Immediately after the completion of preoperative chemotherapy or the date of discontinuation.
measure: QOL assessment (LARS score, EORTC QLQ-C30, and SF-36)
timeFrame: 3 years
measure: Incidence of preoperative treatment-related adverse events
timeFrame: Immediately after the completion of preoperative chemotherapy or the date of discontinuation.
measure: Pathological complete response (pCR) rate in the surgical subgroup
timeFrame: Immediately after the evaluation of the histopathological findings after surgery
measure: Radical resection rate in the surgical subgroup
timeFrame: 3 years (up to 5 years)
measure: Local recurrence-free survival (LRFS) in the surgical subgroup
timeFrame: 3 years (up to 5 years)
measure: Surgery-related adverse event rate determined by Clavien-Dindo classification v2.0 in the surgical subgroup
timeFrame: For early (within 30 days) and late (31-90 days) postoperative adverse events after the end of surgical therapy
measure: Local re-enlargement rate in the NOM subgroup
timeFrame: 3 years (up to 5 years)
measure: Time for local regrowth in the NOM subgroup
timeFrame: 3 years (up to 5 years)
measure: Proportion of salvage surgery in local re-enlargement cases in the NOM subgroup
timeFrame: 3 years (up to 5 years)
measure: Time until salvage surgery in the NOM subgroup
timeFrame: 3 years (up to 5 years)
measure: Surgery-related adverse event rate determined by Clavien-Dindo classification v2.0 in salvage surgery cases in the NOM subgroup
timeFrame: For early (within 30 days) and late (31-90 days) postoperative adverse events after the end of surgical therapy
measure: Proportion of radical resection in salvage surgery cases in the NOM subgroup
timeFrame: 3 years (up to 5 years)
Other outcomes:
measure: liquid biopsy
timeFrame: 3 years (up to 5 years)
measure: Artificial Intelligence (AI) (deep learning) analysis
timeFrame: 3 years (up to 5 years)
Locations:
city: Chiba
country: Japan
facility: National Cancer Center Hospital East
city: Ehime
country: Japan
facility: Ehime Prefectural Central Hospital
city: Fukuoka
country: Japan
facility: Kyushu University Hospital
city: Fukuoka
country: Japan
facility: National Hospital Organization Kyushu Cancer Center
city: Fukuoka
country: Japan
facility: National Hospital Organization Kyushu Medical Center
city: Gifu
country: Japan
facility: Gifu University Hospital
city: Hirosaki
country: Japan
facility: Hirosaki University Hospital
city: Hiroshima
country: Japan
facility: Hiroshima University Hospital
city: Kawasaki
country: Japan
facility: St. Marianna University Hospital
city: Kitakyushu
country: Japan
facility: University of Occupational and Environmental Health Hospital
city: Kochi
country: Japan
facility: Kochi Medical School Hospital
city: Kumamoto
country: Japan
facility: Kumamoto University Hospital
city: Kyoto
country: Japan
facility: Kyoto Prefectural University of Medicine
city: Nagoya
country: Japan
facility: Nagoya University Hospital
city: Okayama
country: Japan
facility: Ohara Memorial Kurashiki Central Medical Organization Kurashiki Central Hospital
city: Okayama
country: Japan
facility: Okayama University Hospital
city: Osaka
country: Japan
facility: Kansai Medical University Hospital
city: Osaka
country: Japan
facility: Kindai University Hospital
city: Osaka
country: Japan
facility: National Hospital Organization Osaka Medical Center
city: Osaka
country: Japan
facility: Osaka International Cancer Institute
city: Osaka
country: Japan
facility: Osaka Metropolitan University Hospital
city: Osaka
country: Japan
facility: Osaka Prefectural Hospital Organization Osaka Acute and General Medical Center
city: Osaka
country: Japan
facility: Osaka University Hospital
city: Sagamihara
country: Japan
facility: Kitasato University Hospital
city: Sapporo
country: Japan
facility: Sapporo Medical University Hospital
city: Tokyo
country: Japan
facility: Keio University Hospital
city: Tokyo
country: Japan
facility: National Cancer Center Hospital
city: Tokyo
country: Japan
facility: Nippon Medical School Hospital
city: Tokyo
country: Japan
facility: Tokyo Medical University Hospital
city: Tokyo
country: Japan
facility: Tokyo Metropolitan Hospital Organization Tokyo Metropolitan Komagome Hospital
city: Yokohama
country: Japan
facility: Kanagawa Prefectural Hospital Organization Kanagawa Cancer Center
city: Yokohama
country: Japan
facility: Yokohama City University Hospital
city: Yokohama
country: Japan
facility: Yokohama City University Medical Center
city: Yokosuka
country: Japan
facility: Federation of National Public Service Personnel Mutual Aid Associations Yokosuka Mutual Aid Hospital
Study officials:
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.