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

Overview

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.

Interventions

• Radiation SCRT
  5x5 Gy: 25 Gy
• 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
• 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

Primary outcome measures

• Organ-preservation adapted DFS [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 measures (12)

• cCR rate [Time frame: 1-3 weeks (Days 7-21) from the completion of preoperative chemotherapy or the date of discontinuation.]
• Clinical response (cCR+near CR [nCR]) rate [Time frame: Within 1-3 weeks (Days 7-21) from the completion of preoperative chemotherapy or the date of discontinuation.]
• Proportion of NOM selection [Time frame: 3-6 weeks (Days 21-42) from the completion of preoperative chemotherapy or the date of discontinuation.]
• Recurrence type and recurrence rate [Time frame: 3 years (up to 5 years)]
• Distant metastases free survival (DMFS) [Time frame: 3 years (up to 5 years)]
• Local recurrence-free survival (LRFS) [Time frame: 3 years (up to 5 years)]
• Overall survival (OS) [Time frame: 3 years (up to 5 years)]
• TME-free survival [Time frame: 3 years (up to 5 years)]
• TME-free DFS [Time frame: 3 years (up to 5 years)]
• Protocol treatment completion rate [Time frame: Immediately after the completion of preoperative chemotherapy or the date of discontinuation.]
• Relative dose intensity (RDI) [Time frame: Immediately after the completion of preoperative chemotherapy or the date of discontinuation.]
• QOL assessment (LARS score, EORTC QLQ-C30, and SF-36) [Time frame: 3 years]

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Japan · 34 centers

• National Cancer Center Hospital East — Chiba
• Ehime Prefectural Central Hospital — Ehime
• Kyushu University Hospital — Fukuoka
• National Hospital Organization Kyushu Cancer Center — Fukuoka
• National Hospital Organization Kyushu Medical Center — Fukuoka
• Gifu University Hospital — Gifu
• Hirosaki University Hospital — Hirosaki
• Hiroshima University Hospital — Hiroshima
• … and 26 more centers

Publications

• Watanabe J, Kagawa Y, Chida K, Ando K, Kotani D, Oba K, Bando H, Hojo H, Shimamoto S, Sakashita S, Kuwata T, Tsuboyama T, Hosomi N, Uemura M, Uehara K, Ito M, Oki E, Takemasa I, Misugi E, Sledge G, Sumani K, Imoto S, Kato T, Yoshino T. Phase III trial of short-course radiotherapy followed by CAPOXIRI versus CAPOX in locally advanced rectal cancer: the ENSEMBLE trial. ESMO Gastrointest Oncol. 2023 PMID 41647286
• 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. PMID 38485756
• 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. PMID 39116386
• 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. PMID 37927927
• 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. PMID 39502728

Identifiers

NCT: NCT05646511 · K2022001 · jRCTs031220342

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗