Short-course Neoadjuvant Radiotherapy Combined With Chemotherapy and Iparomlimab and Tuvonralimab in Microsatellite Stability (MSS) or Mismatch-repair-proficient (pMMR) Patients With Locally Advanced Rectal Cancer: A Randomized Controlled Clinical Study
Colorectal cancer ranks as the third most prevalent malignancy worldwide and the second leading cause of cancer-related mortality. For patients with locally advanced rectal cancer (LARC) classified as T3-4/N+ without distant metastasis, achieving organ preservation and functional integrity while pursuing curative treatment remains a formidable clinical challenge. This study aims to evaluate the efficacy and organ preservation rates of a novel neoadjuvant regimen comprising short-course radiotherapy followed by four cycles of CAPEOX combined with Iparomlimab and Tuvonralimab in patients with microsatellite stable (MSS) or mismatch repair proficient (pMMR) LARC. Furthermore, the project will investigate potential predictive biomarkers for complete response (CR) within this immunotherapy-based total neoadjuvant therapy (iTNT) paradigm.
• Sign a written Informed Consent Form (ICF) and be able to comply with the visits and related procedures stipulated in the protocol
• Age between 18 and 75 years old
• Histologically confirmed rectal adenocarcinoma
• According to the AJCC 8th Edition staging, imaging evaluation (enhanced CT or enhanced MRI) confirms resectable locally advanced rectal cancer (AJCC 8th Edition staging cT3-4 / cN+)
• Patients with microsatellite stability (MSS) or proficient mismatch repair (pMMR) rectal cancer
• At least one evaluable lesion according to RECIST v1.1 criteria
• Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 to 1
• Adequate organ and bone marrow function, defined as follows:
‣ Blood count: Absolute Neutrophil Count (ANC) ≥1.5×10\^9/L; Platelet (PLT) ≥100×10\^9/L; Hemoglobin (HGB) ≥10.0 g/dL.
⁃ Liver function: Total Bilirubin (TBIL) ≤1.5×Upper Limit of Normal (ULN); Alanine transaminase (ALT) and Aspartate transaminase (AST) ≤3×ULN. Serum albumin (ALB) ≥35 g/L.
⁃ Renal function: Serum creatinine ≤1.5×ULN or creatinine clearance ≥50 ml/min (calculated using the Cockcroft-Gault formula or standard 24-hour urine collection method); Urine dipstick test shows urine protein \<2+; For subjects with baseline urine dipstick test showing urine protein ≥2+, a 24-hour urine collection should be performed, and the protein content in the 24-hour urine should be \<1 g.
⁃ Coagulation function: International Normalized Ratio (INR) ≤1.5, and Activated Partial Thromboplastin Time (APTT) ≤1.5×ULN. Certain anticoagulant drugs (such as antiplatelet drugs, vitamin K antagonists, etc.) need to be discontinued 7\
∙ 14 days before surgery and replaced with other drugs (such as low molecular weight heparin)
• No serious concomitant diseases that threaten the subject's survival (resulting in an expected survival time of less than 5 years)
⁃ Female subjects of childbearing potential or male subjects with partners of childbearing potential must use effective contraception throughout the treatment period and for 6 months after the treatment period. Female subjects must have evidence of postmenopausal status or a negative urine or serum pregnancy test result for premenopausal female subjects.