SCRT + Fruquintinib + Tislelizumab + CAPOX Versus SCRT + Tislelizumab + CAPOX as Neoadjuvant Therapy for Locally Advanced Low Rectal Cancer

Prior treatment

• Has received or is receiving any of the following treatments:
  • Use of immunosuppressive agents or systemic corticosteroids for immunosuppression within 2 weeks before the first study drug administration (dose \> 10 mg/day prednisone or equivalent); inhaled or topical steroids and adrenal corticosteroid replacement at doses \> 10 mg/day prednisone equivalent are permitted in the absence of active autoimmune disease;
  • Receipt of a live attenuated vaccine within 4 weeks before the first study drug administration;
  • Major surgery or severe trauma within 4 weeks before the first study drug administration.
• Severe infection (CTCAE \> grade 2) within 4 weeks before the first study drug administration, such as severe pneumonia, bacteremia, or infectious complications requiring hospitalization; active pulmonary inflammation on baseline chest imaging, or signs/symptoms of infection or need for oral/intravenous antibiotics within 14 days before the first study drug administration, except for prophylactic antibiotic use.
• As judged by the investigator, other factors that may lead to forced discontinuation of the study, such as other serious diseases (including psychiatric disorders) requiring concomitant treatment, alcoholism, drug abuse, family or social factors, or any factor that may affect the subject's safety or compliance.

Other illness

• History of allergy to any anti-angiogenic targeted drug, any component of monoclonal antibodies, capecitabine, oxaliplatin, or other platinum-containing agents.
• Any active autoimmune disease or history of autoimmune disease, including but not limited to: interstitial pneumonia, enteritis, hepatitis, hypophysitis, vasculitis, nephritis, hyperthyroidism, hypothyroidism (may be considered for enrollment after hormone replacement therapy); subjects with psoriasis or childhood asthma/allergy that has completely resolved and requires no intervention after adulthood may be considered for enrollment, but those requiring bronchodilator medical intervention are excluded.
• History of immunodeficiency, including positive HIV test, or other acquired or congenital immunodeficiency diseases, or history of organ transplantation or allogeneic bone marrow transplantation.
• Active pulmonary tuberculosis infection identified by history or CT, or history of active pulmonary tuberculosis within 1 year before enrollment, or history of active pulmonary tuberculosis more than 1 year ago without standard treatment.
• Active hepatitis B (HBV DNA ≥ 2000 IU/mL or 10⁴ copies/mL), or hepatitis C (positive anti-HCV antibody and HCV RNA above the lower limit of detection of the assay).
• Presence of a second primary malignancy.
• Arterial or venous thrombotic events within 6 months, such as cerebrovascular accident (including transient ischemic attack), deep vein thrombosis, and pulmonary embolism.
• History of substance abuse that cannot be discontinued, or psychiatric disorders.
• Any signs or history of bleeding diathesis, regardless of severity.
• Patients with active bleeding or a tendency to bleed indicating high bleeding risk.

Lab values

• Uncontrolled cardiac clinical symptoms or diseases, including but not limited to: (1) heart failure of NYHA class II or higher, (2) unstable angina, (3) myocardial infarction within 1 year, (4) clinically significant supraventricular or ventricular arrhythmia that remains uncontrolled with or without clinical intervention, (5) hypertension not well controlled by a single antihypertensive agent (systolic blood pressure ≥ 150 mmHg, diastolic blood pressure ≥ 100 mmHg) or requiring two or more antihypertensive agents, (6) New York Heart Association (NYHA) cardiac function class \> II or left ventricular ejection fraction (LVEF) \< 50%.

Other

• Pregnant or lactating women.
• Urinalysis showing proteinuria ≥ ++, confirmed by 24-hour urine protein quantification \> 1.0 g.

• Has voluntarily signed a written informed consent form before any study-specific procedures.
• Age 18 to 75 years (inclusive), with no restriction on sex.
• Histologically confirmed locally advanced rectal adenocarcinoma by biopsy.
• Pelvic MRI shows high-risk features, meeting any one of the following:
  • Clinical tumor (cT) stage cT4a or cT4b (per AJCC 8th edition);
  • Extramural venous invasion (EMVI);
  • Clinical nodal (cN) stage cN2 (per AJCC 8th edition);
  • Involvement of the mesorectal fascia (MRF);
  • Enlarged lateral lymph nodes.
• The inferior margin of the tumor is ≤ 10 cm from the anal verge.
• Able to swallow tablets and capsules normally.
• ECOG performance status 0-1.
• No prior anti-tumor treatment for rectal cancer, including radiotherapy, chemotherapy, or surgery.
• Planned to undergo surgical treatment after completion of neoadjuvant therapy.
• No contraindications to surgery.
• Adequate function of major organs, including:
  • Hematology (no blood or blood-product transfusion, and no use of G-CSF or other hematopoietic growth factors for correction within 14 days before the first treatment): absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L; platelet count ≥ 75 × 10⁹/L; hemoglobin ≥ 90 g/L; white blood cell count ≥ 3.0 × 10⁹/L;
  • Blood chemistry: total bilirubin ≤ 1.5 × ULN (for subjects with Gilbert's syndrome, ≤ 3 × ULN; for those with liver metastases, total bilirubin ≤ 3 × ULN); ALT ≤ 2.5 × ULN and AST ≤ 2.5 × ULN (for those with liver metastases, ≤ 5 × ULN); serum creatinine ≤ 1.5 × ULN, or creatinine clearance ≥ 50 mL/min ;
  • Coagulation: International Normalized Ratio (INR) ≤ 1.5 × ULN; activated partial thromboplastin time (APTT) ≤ 1.5 × ULN; prothrombin time (PT) ≤ 1.5 × ULN;
  • Doppler ultrasound assessment: left ventricular ejection fraction (LVEF) ≥ 50%.
• Female subjects of childbearing potential must have a serum pregnancy test within 14 days before the first study drug administration, with a negative result, and must use effective contraception (e.g., intrauterine device, contraceptive pills, or condoms) during the study and for at least 6 months after the last dose. Male subjects whose partners are women of childbearing potential must use effective contraception during the study and for 6 months after the last dose.