Short-course Radiotherapy Followed by Fruquintinib Plus Adebrelimab and CAPOX in the Full Course Neoadjuvant Treatment of Locally Advanced Rectal Cancer: a Multicenter, Single-arm, Open-label Study

Inclusion Criteria:

1. Signed written informed consent and volunteered to participate in the study;
2. Age 18-75 years old (including the cut-off value), male or female;
3. Locally advanced rectal adenocarcinoma confirmed by histopathology;
4. High risk on pelvic MRI [one of the following criteria] :

• Clinical tumor (cT) stage cT4a or cT4b (according to the AJCC, 8th edition)
• Extramural vascular infiltration
• Clinical lymph node (cN) stage cN2 (according to the AJCC, 8th edition)
• Involvement of the mesenteric fascia
• Enlarged lateral lymph nodes

5. The distance between the lower edge of the tumor and the anal edge is ≤10cm;
6. Able to swallow tablets and capsules normally;
7. ECOG PS 0-1
8. Have not received any anti-tumor treatment for rectal cancer, including surgery,radiotherapy, chemotherapy, targeted therapy, immunotherapy, etc.
9. Plan to undergo surgery after completion of total neoadjuvant therapy;
10. No surgical contraindications;
11. Normal major organ function, including:
12. Routine blood test (no blood transfusion and blood products within 14 days priorto the first treatment, no correction with G-CSF and other hematopoieticstimulating factors) :

• Neutrophil count ≥ 1.5×109/L
• Platelet count ≥ 100×109/L
• Hemoglobin ≥ 90 g/L
• White blood cell count ≥ 3.0×109/L

2. Blood biochemical tests:

• Total bilirubin ≤ 1.5×ULN (Gilbert's syndrome subjects, ≤3×ULN; Tumor livermetastasis, total bilirubin ≤3×ULN)
• ALT ≤ 2.5×ULN, AST ≤ 2.5×ULN (≤5×ULN for patients with liver metastases)
• Serum creatinine ≤ 1.5×ULN, or creatinine clearance ≥ 50 mL/min (Cocheroft-Gault formula, see Annex 2)

3. Coagulation function:

• International Normalized ratio (INR) ≤ 1.5×ULN
• Activated partial thromboplastin time (APTT) ≤ 1.5×ULN
• Prothrombin time (PT) ≤1.5×ULN

4. Doppler ultrasound assessment: left ventricular ejection fraction (LVEF)≥50%
5. Female subjects of childbearing potential were required to have a negative serumpregnancy test within 14 days before starting the trial drug and to have used aneffective contraceptive method (e.g., an intrauterine device, contraceptive pill, orcondom) during the trial and for at least 6 months after the last dose; Maleparticipants whose partner is a woman of childbearing potential should use effectivecontraception during the trial and for 6 months after the last dose;

Exclusion Criteria:

1. Previous allergic history to any anti-angiogenesis targeted drug, any component ofmonoclonal antibody, capecitabine, oxaliplatin, or other platinum drugs;
2. Have received or are receiving any of the following:

• being treated with an immunosuppressive drug, or systemic hormone, forimmunosuppression within 2 weeks before the first dose of the study drug (dose> 10mg/ day prednisone or equivalent); Inhaled or topical steroid use anddosage are allowed in the absence of active autoimmune disease; Prednisone 10mg/day or equivalent dose of adrenocortical hormone replacement;
• received live attenuated vaccine within 4 weeks before the first dose of studydrug;
• major surgery or severe trauma within 4 weeks before the first dose of studydrug;

3. Have any active autoimmune disease or history of autoimmune disease, including but notlimited to: interstitial pneumonia, enteritis, hepatitis, hypophysitis, vasculitis,nephritis, hyperthyroidism, hypothyroidism (may be considered after hormonereplacement therapy); Patients with psoriasis or complete remission of childhoodasthma/allergies without any intervention in adulthood were considered for inclusion,but patients requiring medical intervention with bronchodilators were not included.
4. A history of immunodeficiency, including HIV positive, other acquired or congenitalimmunodeficiency diseases, or organ transplantation or allogeneic bone marrowtransplantation;
5. The presence of uncontrolled cardiac symptoms or diseases, including but not limitedto: (1) heart failure above NYHA class II, (2) unstable angina, (3) myocardialinfarction within 1 year, (4) clinically significant supraventricular or ventriculararrhythmias without or poorly controlled after clinical intervention; (5) patientswith hypertension that is not well controlled with a single antihypertensive drug (systolic blood pressure ≥150 mmHg, diastolic blood pressure ≥100mmHg), or patientsusing two or more antihypertensive drugs to control blood pressure; (6) New York HeartAssociation (NYHA) functional class &gt; Grade II or left ventricular ejectionfraction (LVEF) < 50%;
6. Severe infection (CTCAE > 2) occurred within 4 weeks before the first dose of studydrug, such as severe pneumonia requiring hospitalization, bacteremia, and infectiouscomplications; Prophylactic antibiotics were excluded if there was active pulmonaryinflammation on baseline chest imaging, if there were signs and symptoms of infectionwithin 14 days before the first dose of study drug, or if oral or intravenousantibiotics were required;
7. Patients with active pulmonary tuberculosis infection detected by medical history orCT examination, or with a history of active pulmonary tuberculosis infection within 1year before enrollment, or with a history of active pulmonary tuberculosis infectionmore than 1 year before enrollment but without regular treatment;
8. Presence of active hepatitis B (HBV DNA ≥ 2000 IU/mL or 104 copies/mL), hepatitis C (hepatitis C antibody positive, and HCV RNA above the detection limit of theanalytical method);
9. The patient had a second primary malignancy;
10. Pregnant or lactating women;
11. History of arterial/venous thrombosis events within 6 months, such as cerebrovascularaccident (including transient ischemic attack), deep vein thrombosis and pulmonaryembolism;
12. Persons with a history of psychotropic drug abuse and inability to quit or with mentaldisorders;
13. Patients with any constitutional sign or history of bleeding regardless of severity;
14. Patients with high risk of bleeding, such as active bleeding or bleeding tendency;
15. Urine routine test showed urine protein ≥++, and confirmed 24-hour urine proteinquantitation > 1.0 g;
16. According to the investigator's judgment, there are other factors that may lead to theforced termination of the study, such as other serious diseases (including mentaldiseases) requiring combined treatment, alcohol abuse, drug abuse, family or socialfactors, and factors that may affect the safety or compliance of the subjects.