Background: Non-operative management (NOM) may enable more patients (pts) with a complete clinical response (cCR) or near-complete clinical response (nCR) after total neoadjuvant therapy (TNT) for locally advanced rectal cancer (LARC) to avoid subsequent radical surgery, possibly maintaining the anorectal function and quality of life (QoL). The PRODIGE-23 trial demonstrated that triplet regimen before chemoradiotherapy (CRT) significantly improved outcomes in comparison to CRT. However, there have been no prospective studies of consolidation triplet versus doublet regimens following short course radiotherapy (SCRT). This randomized phase III trial aimed to test the superiority of consolidation CAPOXIRI vs. CAPOX after SCRT as TNT in pts with LARC. Methods: Pts of >18 years of age, with an ECOG PS of 0-1, biopsy-proven newly diagnosed primary LARC (<12 cm from anal verge [AV]), stage cT3-4N0M0 or cTanyN1-2M0 are eligible for inclusion. Pts with known MSI-H or dMMR are excluded. Eligible pts are centrally randomized (1:1) by the minimization method with stratification by institution, cT1-3 vs. cT4, cN- vs. cN+ and AV of < 5 vs. >5 cm. The experimental treatment group receives SCRT (5 × 5 Gy) followed by six cycles of CAPOXIRI (capecitabine 800 mg/m² [orally, twice daily, day 1-14], oxaliplatin 130 mg/m² [intravenously, day 1] and irinotecan 200 mg/m² [intravenously, day 1, q3wks]). The standard-of-care group receives SCRT (5 × 5 Gy) followed by six cycles of CAPOX (capecitabine 1000 mg/m² [orally, twice daily, day 1-14], oxaliplatin 130 mg/m² [intravenously, day 1, q3wks]). All patients will be restaged after completing TNT before radical surgery according to the Memorial Sloan Kettering Regression Schema; pts with an incomplete response (iCR) will undergo total mesorectal excision (TME), cCR pts will receive NOM, and nCR pts will undergo TME or NOM at the physician’s 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, then every 6 months to 5 years. The primary endpoint is organ preservation-adapted disease-free survival (DFS) in the intention-to-treat population. To detect a decrease in 3-year cumulative probability of organ preservation-adapted DFS from 75.0% to 80.6%, corresponding to a target hazard ratio of 0.75, 608 pts (196 events) would achieve 70% power at a two-sided α of 0.05. Key secondary endpoints include DFS, overall survival, adverse events and QoL. Translational research includes genomic profiling with whole genome/transcriptome sequencing of tissue and blood samples, and the establishment of NOM predictor by deep learning. This study will start in October 2022. Clinical trial information: jRCTs031220342.