SCRT Combined With Chemotherapy and Iparomlimab and Tuvonralimab in MSS or pMMR Patients With Locally Advanced Rectal Cancer

Exclusion Criteria

• •1. Patients with rectal cancer who have been tested for microsatellite instability as MSI-H or mismatch repair as dMMR
• •2. Patients who have previously received any anti-tumor treatment for the studied disease, including surgery, radiotherapy, chemotherapy, targeted therapy, immunotherapy, etc. This includes previous treatment with anti-PD-1, anti-PD-L1, anti-programmed death receptor ligand 2 (PD-L2) or anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) drugs, or any other drugs acting on T cell co-stimulation or immune checkpoint pathways (such as OX40, CD137, etc.), as well as adoptive cell immunotherapy
• •3. Simultaneous participation in another clinical study, unless participating in an observational (non-interventional) clinical study or in the survival follow-up phase of an interventional study
• •4. Treatment with any investigational drug or device within 4 weeks prior to the first dose of the study drug
• •5. History of blood transfusion within 14 days before the screening laboratory tests, or use of Granulocyte-colony stimulating factor (G-CSF), Granulocyte-Macrophage-colony stimulating factor (GM-CSF), erythropoietin (EPO), thrombopoietin (TPO), or IL-11
• •6. Use of immunosuppressive drugs within 4 weeks prior to the first dose of the study drug, excluding: intranasal inhaled local steroid therapy or local steroid injections (such as intra-articular injections); systemic corticosteroid therapy not exceeding 10 mg/day of prednisone or its equivalent physiological dose; glucocorticoids as preventive medication for allergic reactions (such as pre-CT medication); use of Chinese herbal medicine or immunomodulatory drugs with anti-tumor indications (including thymosin, interferon, interleukin, etc.) within 1 week prior to the first dose of the study drug
• •7. Receipt of live or attenuated live vaccines within 4 weeks prior to the first dose of the study drug or expected during the study period
• •8. Major surgical procedures (such as craniotomy, thoracotomy, or laparotomy) within 4 weeks prior to the first dose of the study drug, anticipated need for major surgery during the study treatment period (except for radical rectal cancer surgery as specified in the protocol), or presence of unhealed wounds, ulcers, or fractures
• •9. Known active or suspected autoimmune disease or history of autoimmune disease within the past 2 years (subjects with eczema, vitiligo, psoriasis, alopecia, or Graves' disease not requiring systemic treatment in the past 2 years, history of hypothyroidism requiring only thyroid hormone replacement therapy or autoimmune hypothyroidism, and type I diabetes requiring only insulin replacement therapy may be enrolled)
• •10. Known history of primary immunodeficiency
• •11. Active tuberculosis, currently receiving anti-tuberculosis treatment or having received anti-tuberculosis treatment within 1 year prior to the first dose of the study drug
• •12. Known history of allogeneic organ transplantation and allogeneic hematopoietic stem cell transplantation
• •13. Known allergy to capecitabine, oxaliplatin, anti-PD-1 monoclonal antibody, anti-CTLA-1 monoclonal antibody, anti-PD-1/CTLA-4 antibody preparation, or other monoclonal antibody components
• •14. Ascites and pleural effusion requiring clinical intervention in the short term, symptomatic or requiring drainage of pericardial effusion
• •15. Human immunodeficiency virus (HIV) infection (HIV antibody positive)
• •16. Acute or chronic active hepatitis B (defined as HBsAg or only HBcAb positive and HBV DNA ≥2000 IU/mL or ≥1×10\^4 copies/mL), acute or chronic active hepatitis C (defined as HCV antibody positive and HCV-RNA level above the lower limit of detection)
• •17. HBV DNA ≥2000 IU/mL or ≥1×10\^4 copies/mL), acute or chronic active hepatitis C (defined as HCV antibody positive and HCV-RNA level above the lower limit of detection)
• •18. Active syphilis infection requiring treatment
• •19. Severe infection occurring within 4 weeks prior to the first dose of the study drug or during the active phase or poorly controlled, including but not limited to hospitalization for infection, bacteremia, or complications of severe pneumonia, therapeutic oral or intravenous antibiotics within two weeks prior to the first dose
• •20. Symptomatic congestive heart failure (New York Heart Association class II\~IV) or left ventricular ejection fraction (LVEF) \<50% on echocardiography; symptomatic or poorly controlled arrhythmia; history of congenital long QT syndrome or corrected QTc \>500 ms at screening (calculated using Fridericia's method)
• •21. Uncontrolled arterial hypertension despite standard treatment (systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg), history of hypertensive crisis or hypertensive encephalopathy
• •22. Severe bleeding tendency or coagulation dysfunction, or undergoing thrombolytic therapy
• •23. Any arterial thromboembolic event within 6 months prior to the first dose of the study drug, including myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack
• •24. Esophageal or gastric varices requiring immediate intervention (e.g., ligation or sclerotherapy) or considered at high risk of bleeding by the investigator or after consultation with a gastroenterologist or hepatologist, evidence of portal hypertension (including splenomegaly on imaging) or history of variceal bleeding, subjects must undergo endoscopic evaluation within 3 months prior to enrollment
• •25. History of gastrointestinal perforation and/or fistula within 6 months prior to the first dose of the study drug
• •26. Any life-threatening bleeding event within 3 months prior to the first dose of the study drug, or grade 3 or 4 gastrointestinal/variceal bleeding event requiring transfusion, endoscopy, or surgical treatment
• •27. History of deep vein thrombosis, pulmonary embolism, or any other severe thromboembolic event within 3 months prior to the first dose of the study drug (implantable venous port or catheter-related thrombosis, or superficial venous thrombosis is not considered "severe" thromboembolism)
• •28. Uncontrolled metabolic disorders or other non-malignant organ or systemic diseases or cancer-related reactions that may lead to higher medical risks and/or uncertainty in survival evaluation
• •29. Hepatic encephalopathy, hepatorenal syndrome, or Child-Pugh class B \>7 points or more severe cirrhosis
• •30. Intestinal obstruction (including incomplete intestinal obstruction requiring parenteral nutrition) and not relieved by the screening period; subjects at risk of intestinal perforation (including but not limited to acute diverticulitis, abdominal abscess, history of abdominal cancer); history of extensive intestinal resection (partial colectomy or extensive small bowel resection, complicated by chronic diarrhea), Crohn's disease, ulcerative colitis, or chronic diarrhea
• •31. Interstitial lung disease requiring treatment; history and current presence of pulmonary fibrosis, pneumoconiosis, drug-related pneumonia, organic pneumonia (such as bronchiolitis obliterans), severe pulmonary impairment, etc.
• •32. Significant malnutrition (weight loss of 5% within 1 month or 15% within 3 months prior to signing the informed consent, or reduction in food intake by 1/2 or more within 1 week), or patients requiring intravenous nutritional support. However, malnutrition corrected more than 4 weeks prior to the first dose of the study drug is excluded
• •33. History of other primary malignancies, except: malignancies that have been cured, with no known active disease for ≥2 years prior to the first dose of the study drug and with a very low risk of recurrence
• •34. Adequately treated non-melanoma skin cancer or malignant lentigo with no evidence of disease recurrence
• •35. Adequately treated carcinoma in situ with no evidence of disease recurrence
• •36. Other acute or chronic diseases that may result in: increased risk related to study participation or study drug administration, or interference with the interpretation of study results, and in the investigator's judgment, render the subject ineligible for participation in this study
• •37. Neurological, psychiatric disorders, or social conditions that: affect compliance with study requirements, significantly increase the risk of adverse events, or affect the subject's ability to provide written informed consent, such as history of schizophrenia, drug abuse, etc.
• •38. Alcohol, drug, or substance use that may hinder drug administration or affect toxicity analysis
• •39. Pregnant or breastfeeding female subjects
• •40. Other situations deemed unsuitable for enrollment by the investigator