Short-course Radiation (SCRT) Followed by 6 Cycles of Cadonilimab Plus MFOLFOX6 As Neoadjuvant Therapy for Patients with Locally Advanced Rectal Cancer (LARC): a Multicenter, Two-arm Parallel, Open-label, Randomised Phase III Trial (NeoCaCRT-III)

Inclusion Criteria:

1. Age ≥18 yeas and ≤79 years. The gender is not limited. 2. Histopathologyconfirmed the diagnosis of rectal adenocarcinoma. 3. Patients with rectalcancer based on endoscopic ultrasound and / or pelvic MRI contrast + contrast,chest CT, head MRI or CT + contrast, or PET / CT, staging criteria per AJCC 8thedition cancer stage, cT 3-T4 / N + M0.

2. At least 20 unstained sections of formalin-fixed paraffin-embedded tumor tissuesections, or fresh tumor tissue, can be provided for genomic and proteomictesting.

3. The Eastern Cooperative Oncology Group Performance status (ECOG PS) 0- 1. 6.Adequate bone marrow and organ function meets the following criteria:

4. Neutrophil count (ANC)≥1.5×l09/L

5. Platelet (PLT) ≥80×109/L

6. Hemoglobin (Hb) level ≥90 g/L

7. Total bilirubin level≤1.5×ULN

8. Alanine aminotransferase (ALT) level≤3×ULN

9. Aspartate aminotransferase (AST) level ≤3×ULN

10. International normalized value (INR) or prothrombin time (PT) or activatedpartial thromboplastin time (aPTT) ≤1.5×ULN

11. Serum creatinine (Cr) level ≤1.5×ULN

12. Creatinine clearance #50 ml/min (Calculated according to the Cockcroft-Gaultformula)

Exclusion Criteria:

1. Previous history of severe hypersensitivity to other monoclonal antibodies orany component of AK 104.

2. Preoperative pathology was diagnosed as squamous cell carcinoma orneuroendocrine tumor 3. Within 5 years before enrollment for malignancies otherthan colorectal cancer with negligible risk of metastasis or death (e. g.,expected 5-year OS> 90%) and expected radical results after treatment (e. g.,adequately treated cervical carcinoma in situ, basal or squamous cell skincarcinoma, localized prostate carcinoma for curative intent, ductal carcinomain situ surgically treated with curative intent).

3. Previous treatment against the PD-1 receptor or its ligand PD-L1 or thecytotoxic T lymphocyte-associated protein-4 (CTLA-4) receptor.

4. History of autoimmune diseases, including but not limited to myasthenia gravis,myoitis, autoimmune hepatitis, series, systemic lupus erythematosus, rheumatoidarthritis, inflammatory bowel disease, vascular thrombosis related toantiphospholipid syndrome, Wegener's granulomatosis, Sjogren's syndrome,Guillain-Barre syndrome, multiple sclerosis, vasculitis, vasculitis, orglomerulnephritis; patients with autoimmune-related hypothyroidism wereeligible for stable-dose thyroid hormone replacement therapy; patients withtype 1 diabetes under control after a stable insulin regimen were eligible toparticipate in this study; 6. Receiving systemic immune stimulation drugs (including but not limited to interferon or IL-2) within 4 weeks prior toenrollment or within 5 half-lives of the drug (whichever is shorter); 7.Received systemic corticosteroids (> 10 mg/d of prednisone equivalent) or othersystemic immunosuppressive agents (including but not limited to prednisone,prednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate,thalidomide, and anti-TNF agents [anti-TNF]) within 2 weeks prior toenrollment. Local, ocular, intra-articular, nasal, and inhaled corticosteroidsare permittedt; 8. Patients requiring baseline and subsequent MRI tumorevaluation with previous allergic reactions to intravenous contrast agents mayuse preventive steroids.

5. Allowing the use of inhaled corticosteroids for chronic obstructive pulmonarydisease, corticosteroid hydrochloride (e. g., flurohydrocortisone) in patientswith orthostatic hypotension, and low-dose corticosteroid maintenance foradrenal cortical insufficiency.

6. Patients with previous allogeneic bone marrow transplantation or previous solidorgan transplantation.

7. Idiopathic pulmonary fibrosis, drug-induced pneumonia, mechanical pneumonia (i.e. bronchiolitis obliterans), history of idiopathic pneumonia or chest CT scanat screening showed evidence of active pneumonia.

8. Any live vaccine (e. g., vaccine against infectious diseases, such as influenzavaccine, varicella vaccine, etc.) within 4 weeks (28 days) before enrollment.13Active infections, including tuberculosis (clinical diagnosis includingclinical history, physical examination and imaging findings, and TB testsperformed per local medical practice), hepatitis B {known HBV surface antigen (HBsAg) positive and HBVDNA 1000 cps / ml}, hepatitis C or humanimmunodeficiency virus (HIV antibody positive).

9. Patients with prior or cured HBV infection (defined as hepatitis B coreantibody [anti-HBc] positive and HbsAg negative) were to be eligible toparticipate in the study only if HBVDNA was negative (HBVDNA˂ 1000 cps / ml).

10. Patients with positive hepatitis C (HCV) antibody are not eligible for thestudy only if polymerase chain reaction shows negative HCVRNA.

11. Clinically meaningful basic medicine, disease (e. g., dyspnea, pneumonia,pancreatitis, poorly controlled, poorly controlled diabetes, infection activeor poorly controlled, or drug or alcohol abuse).

12. Presence of severe neurological or psychiatric disorders, including dementiaand epileptic seizures.

13. He had an NCI-CTCAE grade 2 peripheral neuropathy. 18. Female patients duringpregnancy or lactation. 19. Chronic bowel disease or short bowel syndrome. 20.Dihydropyrimidine dehydrogenase (DPD) enzyme deficiency. 21. Majorcardiovascular diseases, such as New York Heart Association heart disease (grade II or higher), myocardial infarction within 3 months beforerandomization, unstable arrhythmia, or unstable angina pectoris.

14. Patients with known coronary artery disease, congestive heart failure notmeeting the above criteria, or left ventricular ejection fraction <50% musthave an optimized stable medical regimen as determined by the treatingphysician, consulting a cardiologist if required.