Neoadjuvant CAPOX Plus Pucotenlimab Combined With Selective Radiotherapy Versus CAPOX Combined With Selective Radiotherapy in Patients With Locally Advanced Rectal Cancer：A Multicenter, Phase III, Randomized Clinical Trial
This is a multicenter, phase III, randomized controlled trial. Eligible patients with pMMR/MSS locally advanced rectal cancer will be randomized in a 1:1 ratio to either the experimental group or the control group using stratified randomization, with mesorectal fascia (MRF) status as the stratification factor. Patients in the experimental group will receive four cycles of CAPOX plus pucotenlimab. Patients in the control group will receive four cycles of CAPOX alone. Tumor response will then be assessed. Patients with tumor shrinkage ≥20% and no persistent tumor involvement of the mesorectal fascia will proceed directly to surgery. Patients with tumor shrinkage \<20% or persistent MRF-positive disease will receive short-course radiotherapy, followed by two additional cycles of CAPOX plus pucotenlimab in the experimental group or CAPOX alone in the control group. After completion of neoadjuvant treatment, efficacy will be reassessed, and the timing of surgery will be determined according to treatment response. Postoperative adjuvant therapy will be decided by the investigator.
• Age 18 to 75 years.
• Histologically confirmed rectal adenocarcinoma.
• The lower edge of the tumor is ≤12 cm from the anal verge.
• Clinical stage of cT3-4aN0M0 or cT1-4aN+M0 at initial diagnosis.
• Pre-treatment staging methods:
• Required: chest and abdominal CT and pelvic MRI. Optional: endorectal ultrasound or transrectal ultrasonography. For patients with contraindications to MRI, staging may be performed using CT combined with endorectal ultrasound or transrectal ultrasonography.
• pMMR status confirmed by immunohistochemistry on colonoscopic biopsy specimens at the pathology department of the study center, or MSS/MSI-L status confirmed by genetic testing (PCR-based or NGS-based methods).
• ECOG performance status 0-1.
• Voluntary participation in the study with written informed consent provided.
• No prior antitumor treatment for rectal adenocarcinoma, including but not limited to radiotherapy, chemotherapy, or surgery.
• Expected survival of at least 6 months.
⁃ Adequate organ and bone marrow function, as defined below:
∙ Hematologic function No blood transfusion, hematopoietic growth factors, leukocyte-elevating agents, platelet-elevating agents, or anti-anemia therapy are allowed within 14 days before the first dose of study treatment.
∙ Absolute neutrophil count ≥1.5 × 10\^9/L Platelet count ≥100 × 10\^9/L Hemoglobin ≥60 g/L
‣ Biochemical function Serum albumin ≥30 g/L Total bilirubin ≤1.5 × upper limit of normal (ULN) ALT ≤2.5 × ULN AST ≤2.5 × ULN Alkaline phosphatase (ALP) ≤2.5 × ULN Serum creatinine ≤1.5 × ULN, or creatinine clearance (CrCl) ≥50 mL/min
• CrCl may be calculated using the Cockcroft-Gault formula:
• Male: CrCl = ((140-age)×weight)((140 - age) × weight)((140-age)×weight) / (72×serumcreatinine)(72 × serum creatinine)(72×serumcreatinine) Female: CrCl = ((140-age)×weight)((140 - age) × weight)((140-age)×weight) / (72×serumcreatinine)(72 × serum creatinine)(72×serumcreatinine) × 0.85 Weight in kg; serum creatinine in mg/mL. c. Coagulation function International normalized ratio (INR) ≤1.5 d. Urinary protein Urine protein ≤1+ by dipstick If urine protein is ≥2+, a 24-hour urine protein test is required, and patients may be enrolled only if the result is \<1 g/24 h
• For women of childbearing potential, a serum or urine pregnancy test must be performed within 72 hours before the start of study treatment, with a negative result. Such patients must agree to use effective contraception during the study and for at least 120 days after the last dose of study treatment.
• Good compliance and willingness to cooperate with study follow-up.
• Agreement to provide blood, urine, stool, and tumor tissue samples.