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

Study Overview
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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.

Official Title
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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

Conditions
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Locally Advanced Rectal Cancer

Intervention / Treatment
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* Radiation: SCRT
* Drug: CAPOX
* Drug: CAPOXIRI


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: standard arm: 5x5Gy -> 12 wks CAPOX -> restating -> surgery or non-operative management experimental arm: 5x5Gy -> 12 wks CAPOXIRI -> restating -> surgery or non-operative management
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Control arm SCRT+CAPOX<br>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<br>* 5x5 Gy: 25 Gy<br>* Other names: Active Comparator & Experimental;Drug: CAPOX<br>* 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<br>* Other names: Active Comparator;|
| Experimental: Experimental arm SCRT+CAPOXIRI<br>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<br>* 5x5 Gy: 25 Gy<br>* Other names: Active Comparator & Experimental;Drug: CAPOXIRI<br>* 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)<br>* Other names: Experimental;|

What is the study measuring?
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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. | 
| 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 | 
| 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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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