ENSEMBLE

JRCT ID: jRCTs031220342

Registered date:31/10/2022

Basic Information

• Recruitment status: Recruiting
• Health condition(s) or Problem(s) studied: Locally advanced rectal cancer
• Date of first enrollment: 21/11/2022
• Target sample size: 608
• Study type: Interventional
• Intervention(s): The study protocol consists of preoperative treatment with short course radiotherapy (SCRT) and preoperative chemotherapy, and non-operative management (NOM) or surgical treatment based on re-stating. SCRT will be started within 28 days after enrollment in this study and will be irradiated for 5 consecutive days. Preoperative chemotherapy will be initiated 1-3 weeks (days 7-21) after completion of SCRT. Patients will be randomized to SCRT+CAPOX or SCRT+CAPOXIRI group and continue CAPOX or CAPOXIRI for up to 6 cycles following SCRT. Patients will be re-staged between 1-3 weeks (days 7-21) after completion of preoperative chemotherapy (the last day of capecitabine administration) or the date of decision to discontinue chemotherapy. Depending on the response to treatment, NOM or surgical treatment is selected within 3-6 weeks (days 21-42) from the date of completion of preoperative chemotherapy (the last day of capecitabine administration) or the date of decision to discontinue chemotherapy.

Outcome(s)

• Primary Outcome: Organ preservation adapted disease free survival (DFS)

Secondary Outcome

Secondary endpoints
Clinical complete response (cCR) rate
Clinical response (cCR + near CR: nCR) rate
Non operative management (NOM) selection ratio
Recurrence location and recurrence rate
Distant metastasis free survival (DMFS)
Local recurrence free survival (LRFS)
Overall survival (OS)
Total mesorectal excision (TME) -free survival
TME-free disease-free survival
Protocol treatment completion rate
Relative Dose Intensity (RDI)
QOL evaluation (LARS score, EORTC QLQ-C30, SF-36)
Preoperative treatment-related adverse event rate by CTCAE ver5.0

Subgroups evaluation in TME group
Pathological complete response (pCR) rate
Radical resection rate
Local recurrence free survival (LRFS)
Percentage of surgery-related adverse events rate by Clavien-Dindo classification v2.0

Subgroups evaluation in NOM group
Local re-growth rate
Time to local re-growth
Salvage surgery rate in cases of local re-growth
Time to salvage surgery
Percentage of surgery-related adverse events by Clavien-Dindo classification v2.0 in salvage surgery cases
Radical resection rate in salvage surgery cases

Key inclusion & exclusion criteria

• Age minimum: >= 18age old
• Age maximum: Not applicable
• Gender: Both

Include criteria

(1) The subject has been fully informed of the details of the study and his/her written consent has been obtained.
(2) Adenocarcinoma confirmed by histological examination.
(3) No distant metastasis is identified on imaging examination, and radical resection is clinically feasible.
(4) Subject is at least 18 years of age on the date of consent.
(5) ECOG Performance Status (PS) of 0 - 1
(PS 0 if the subject is 70 years of age or older on the date of consent).
(6) The lower margin of the tumor is within 12 cm of the anal verge (AV).
(7) No prior treatment for the tumor.
(8) No prior pelvic radiation therapy, including treatment for other types of cancer.
(9) Subjects with cT3-4N0M0 or T1-4N1-2M0 based on UICC 8th edition.
( For 5cm<AV<=10cm,T3a/bN0M0, EMVI-, MRF clear and 10cm<AV<=12cm,T3a/bN0-1M0, EMVI-, MRF clear, only subjects who refuse surgery are eligible)
(10) UGT1A1 is wild type or single heterozygous.
(11) The following criteria for major organ function within 28 days prior to enrollment are met.
a. Neutrophil count >= 1500/mm3
b. Platelet count >=10.0 x 104 /mm3
c. Hemoglobin concentration >= 9.0 g/dL
d. Total bilirubin <= 2.0 mg/dl
e. AST: less than or equal to 100 IU/L
f. ALT: less than or equal to 100 IU/L
g. Serum creatinine: creatinine clearance>= 30 mL/min

Exclude criteria

(1) Subject has undergone extensive surgery within 4 weeks prior to the start of protocol treatment (excluding colostomy and central venous port).
(2) Complication or previous history of severe pulmonary disease (interstitial pneumonia, pulmonary fibrosis, severe pulmonary emphysema, etc.).
(3) Colorectal stent implantation.
(4) Cardiac pacemaker or other contraindications to MRI.
(5) Subject has severe comorbidities (heart failure, renal failure, liver failure, intestinal paralysis, bowel obstruction, uncontrolled diabetes, active inflammatory bowel disease, etc.).
(6) Prior or concurrent malignancy < 5 years prior to enrolment in study
(7) Pregnant or lactating women, positive pregnancy test or unwillingness to use contraception.
(8) HBs antigen positive or HCV antibody positive. However, if the HCV-RNA is negative, the subject is eligible for enrollment.
(9) Known human immunodeficiency virus (HIV) infection.
(10) Known microsatellite instability - high (MSI-H) or deficient mismatch repair (dMMR).
(11) The applicant does not intend to consent to the "Research on Genetic Profiling and Clinical Significance Using Clinical Specimens from Cancer Subjects" (CONDUCTOR Study)
(12) The investigator or principal investigator judges that the subject is inappropriate for this study.

Related Information

• Primary Sponsor: Yoshino Takayuki
• Source(s) of Monetary Support: Japan Agency for Medical Research and Development