SCRT-NALIRIXELOX+Sintilimab as TNT for High-Risk LARC

• SCRT (Radiation), also known as Short-Course Radiotherapy: 25 Gy / 5 F
• Liposomal Irinotecan (Drug), also known as Nal-IRI, irinotecan liposome: 50 mg/m², intravenously (IV) on Day 1 of each cycle.
• Oxaliplatin (Drug), also known as OX: 85 mg/m², IV on Day 1 of each cycle.
• Capecitabine (Drug), also known as Xeloda: 800 mg/m², orally twice daily from Day 1 to Day 14 of each cycle.
• Sintilimab (Drug), also known as IBI308: 200 mg, IV on Day 1 of each cycle.

Primary outcomes

• Complete Response Rate [6 months]: The proportion of participants achieving either a Pathologic Complete Response (pCR) or a Clinical Complete Response (cCR). pCR is defined as the absence of viable tumor cells in the primary tumor and lymph nodes (ypT0N0) upon pathological examination after surgery. cCR is defined as the absence of residual tumor as confirmed by imaging (MRI/PET-CT) and clinical assessment (e.g., digital rectal exam, endoscopy) in patients who forgo immediate surgery.

Secondary outcomes

• Major Pathological Response (MPR) Rate [6 months]: The proportion of participants who undergo surgery and achieve a major pathological response, defined as the presence of ≤10% residual viable tumor cells in the primary tumor.
• Objective Response Rate (ORR) [6 months]: The proportion of participants who achieve a Best Overall Response of either Complete Response (CR) or Partial Response (PR) according to RECIST v1.1 criteria.
• Disease Control Rate (DCR) [6 months]: The proportion of participants who achieve a Best Overall Response of Complete Response (CR), Partial Response (PR), or Stable Disease (SD) according to RECIST v1.1 criteria.
• Progression-Free Survival (PFS) [3 years]: The time from the start of treatment to the first occurrence of disease progression (radiographically or pathologically confirmed) or death from any cause, whichever occurs first.
• Overall Survival (OS) [5 years]: The time from the start of treatment to death from any cause.
• 3-Year Event-Free Survival (3y-EFS) Rate [3 years]: The Kaplan-Meier estimated proportion of participants who remain event-free at 3 years from treatment start. An event is defined as disease progression, local recurrence, distant metastasis, or death from any cause.
• 3-Year Disease-Free Survival (3y-DFS) Rate [3 years]: The Kaplan-Meier estimated proportion of participants who remain disease-free at 3 years after surgery. Disease-free survival is defined as the time from surgery to the first occurrence of local or distant recurrence or death from any cause.
• Incidence of Adverse Events (AEs) [6 months]: The frequency and severity of all adverse events (AEs), serious adverse events (SAEs), and immune-related adverse events (irAEs), graded according to NCI CTCAE v5.0.

Sex: All, ages: 18 Years to 75 Years

Inclusion Criteria:

* Voluntary Participation: Subjects voluntarily participate in the study, sign the informed consent form, and have good compliance.
* Age and Gender: Age between 18 and 75 years, any gender.
* Pathological Diagnosis: Histologically or cytologically confirmed rectal adenocarcinoma; confirmed mismatch repair proficient (pMMR) or microsatellite stable (MSS) by genetic testing or immunohistochemistry.
* Disease Stage: Assessed as high-risk, mid-low (distance from the anal verge ≤10 cm) locally advanced rectal cancer by colonoscopy, digital rectal exam, or MRI. High-risk definition: Meeting at least one of the following: cT4, extramural vascular invasion (EMVI), tumor deposits, involvement of the mesorectal fascia or intersphincteric plane.
* Prior Treatment: No prior anti-tumor therapy for this rectal cancer (including surgery, radiotherapy, chemotherapy, immunotherapy, or targeted therapy).
* Measurable Lesion: At least one measurable lesion according to RECIST v1.1 criteria.
* Tumor Tissue Sample: Must provide tumor tissue samples for biomarker analysis.
* Adequate Organ Function (within 7 days before the first dose): 1) Hematological: Hemoglobin ≥90 g/L; White Blood Cell count ≥3.0 x 10⁹/L; Absolute Neutrophil Count ≥1.5 x 10⁹/L; Platelets ≥100 x 10⁹/L. 2) Hepatic: Total Bilirubin <1.5 x ULN; AST and ALT ≤2.5 x ULN; Albumin ≥30 g/L. 3) Renal: Serum Creatinine ≤1.5 x ULN OR Creatinine Clearance ≥50 mL/min. 4) Coagulation: INR ≤1.5 x ULN (or ≤3 x ULN if on stable anticoagulant therapy); PTT or aPTT ≤1.5 x ULN (or ≤3 x ULN if on stable anticoagulant therapy).
* Performance Status: Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
* Life Expectancy: Expected survival time ≥3 months.
* Good organ function.
* Contraception: Subjects of childbearing potential must agree to use effective contraception during the treatment period and for 6 months after the last dose.

Exclusion Criteria:

* Other Malignancies: Diagnosis of another malignancy within 5 years prior to the first dose, except for adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, carcinoma in situ, localized prostate cancer, or papillary thyroid cancer, etc.
* Allergy: Known or suspected allergy to the study drugs or any of their excipients.
* Pregnancy and Lactation: Pregnant or lactating women, or women planning to become pregnant during the study or within 6 months after the last dose.
* Central Nervous System Disease: Known active epilepsy, active central nervous system (CNS) metastases, spinal cord compression, carcinomatous meningitis, or leptomeningeal disease.
* Significant Cardiovascular Disease: Clinically significant uncontrolled cardiovascular disease.
* History of Allergic Disease: History of allergic diathesis, asthma, or atopic dermatitis.
* Pleural Effusion/Ascites: Presence of significant pleural effusion or ascites.
* Active Autoimmune Disease: Active autoimmune disease requiring systemic treatment within 2 years prior to the first dose (replacement therapy is allowed).
* Immunosuppressant Use: Use of systemic corticosteroids (>10 mg/day prednisone equivalent) or other immunosuppressants within 2 weeks prior to enrollment.
* Interstitial Lung Disease: History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or evidence of active pneumonia on screening chest CT scan.
* Transplantation History: History of allogeneic organ transplantation or hematopoietic stem cell transplantation.
* Active Infection: Positive HIV test result; Active Hepatitis B (HBV DNA ≥10⁴ copies/mL); Active Hepatitis C (HCV RNA ≥10³ copies/mL); Active Tuberculosis.
* Gastrointestinal Risk: History of bowel obstruction within 28 days prior to the first study dose; High risk of gastrointestinal perforation.
* Recent Major Surgery: Major surgical procedure within 4 weeks prior to enrollment.
* Other Exclusionary Conditions: Any other acute or chronic disease, mental disorder, or laboratory abnormality that, in the investigator's judgment, may increase the risk associated with study participation or drug administration, or interfere with the interpretation of study results.

• Hongli Liu, Professor, Principal investigator, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology