Neoadjuvant Cadonilimab Plus Chemotherapy Following Short-Course Radiotherapy in Locally Advanced Rectal Cancer

The goal of this clinical trial is to test the efficacy and safety in patients with locally advanced middle and lower rectal cancer. The main questions it aims to answer are:• Whether Cadonilimab combined with chemotherapy following short-course radiation can improve pathological complete response(pCR) rate? •Are the toxicities of the combination therapy manageable? Participants will be given radiation of 5 Gy for 5 days and then neoadjuvant Cadonilimab combined with modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) for 6 cycles. Without progressed disease, total mesorectal excision (TME) or transanal local excision will be performed. If clinical complete response was received, watch and wait strategy is one of choices. Adjuvant Cadonilimab plus mFOLFOX6 for another 6 cycles could be suggested for non-pCR participants,while surveillance is also suitable for pCR ones.

Long-term synchronous chemoradiation (CRT) with sequential TME is the treatment recommended by current guidelines for locally advanced rectal cancer (LARC). The latest STELLAR study showed that preoperative short-course radiotherapy (SCRT) combined with preoperative chemotherapy is safe and effective and can be used as an alternative to conventional CRT in LARC \[1\]. In recent years, new therapies blocking immune checkpoints (cytotoxic T lymphocyte-associated molecular protein 4 (CTLA-4), programmed cell death 1 (PD1) and programmed cell death ligand 1 (PD-L1)) have achieved landmark achievements in the field of cancer therapy. Several clinical trials are evaluating the efficacy of a combination of RT and immune checkpoint inhibitors (ICIs) in rectal cancer (NCT02948348, NCT04124601, NCT04558684). The results of the study suggest that radioimmunotherapy is safe and effective in rectal cancer. A number of studies have shown that combined PD-1 and CTLA-4 blockade is associated with a higher response rate whereas more toxicities in multiple tumor types. Cadonilimab is a tetrameric PD-1/CTLA-4 bispecific antibody, based on the Akeso Tetrabody platform. It introduces novel T cell targeting mechanisms of action that may provide an improved therapeutic index and a favorable toxicity profile compared to PD-1 and CTLA-4 combination therapy. The study of SCRT combined with Cadonilimab and chemotherapy in middle and lower LARC has not been reported at home or abroad.

Therefore, this study plans to recruit 27 patients with middle and lower LARC to explore the efficacy and safety of radiation of 5 Gy for 5 days followed by Cadonilimab 6mg/kg plus mFOLFOX6 (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, 5-fluorouracil bolus 400 mg/m2 on day 1, and 5-fluorouracil infusion 2400 mg/m2 for 48 h) every 2 weeks for total 6 cycles preoperatively. The primary endpoint is the pathological complete response (pCR) after surgery. The secondary endpoints consist of a clinical complete response (cCR), major pathological response (MPR), objective response rate (ORR), recurrence-free survival (RFS), overall survival (OS) and safety. Clinical response was evaluated by endoscopy, digital rectal examination and pelvic MRI. Safety was analyzed in all patients who receive at least one dose of treatment. The exploratory endpoint covers the quality of life.

After surgery, non-pCR patients receive adjuvant Cadonilimab combined with mFOLFOX6 for 6 cycles while pCR ones have two options: adjuvant treatment which is the same as the neoadjuvant regimen or observation. As for cCR patients, TME or transanal local excision is one of options while the watch and wait (W\&W) strategy can also be considered especially for ultra-low rectal cancer.

Eligibility Criteria:
Inclusion Criteria:

1. Age ≥18 yeas and ≤79 years. The gender is not limited.
2. Histopathology confirmed the diagnosis of rectal adenocarcinoma.
3. Patients with rectal cancer based on endoscopic ultrasound and / or pelvic MRI contrast + contrast, chest CT, head MRI or CT + contrast, or positron emission tomography / computed tomography （PET / CT）, staging criteria per American Joint Committee on Cancer (AJCC) 8th edition cancer stage, cT 3-T4 / N + M0.
4. At least 20 unstained sections of formalin-fixed paraffin-embedded tumor tissue sections, or fresh tumor tissue, can be provided for genomic and proteomic testing.
5. The Eastern Cooperative Oncology Group Performance status (ECOG PS) 0- 1.
6. Adequate bone marrow and organ function meets the following criteria:

   1. Neutrophil count (ANC)≥1.5×l09/L
   2. Platelet (PLT) ≥80×109/L
   3. Hemoglobin (Hb) level ≥90 g/L
   4. Total bilirubin level≤1.5×ULN
   5. Alanine aminotransferase (ALT) level≤3×ULN
   6. Aspartate aminotransferase (AST) level ≤3×ULN
   7. International normalized value (INR) or prothrombin time (PT) or activated partial thromboplastin time (aPTT) ≤1.5×ULN
   8. Serum creatinine (Cr) level ≤1.5×ULN
   9. Creatinine clearance #50 ml/min (Calculated according to the Cockcroft-Gault formula)

Exclusion Criteria:

1. Previous history of severe hypersensitivity to other monoclonal antibodies or any component of Cadonilimab.
2. Preoperative pathology was diagnosed as squamous cell carcinoma or neuroendocrine tumor
3. Within 5 years before enrollment for malignancies other than 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 skin carcinoma, localized prostate carcinoma for curative intent, ductal carcinoma in situ surgically treated with curative intent).
4. Previous treatment against the PD-1 receptor or its ligand PD-L1 or the cytotoxic T lymphocyte-associated protein-4 (CTLA-4) receptor.
5. History of autoimmune diseases, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, series, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis related to antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's syndrome, Guillain-Barre syndrome, multiple sclerosis, vasculitis, vasculitis, or glomerulonephritis; patients with autoimmune-related hypothyroidism were eligible for stable-dose thyroid hormone replacement therapy; patients with type 1 diabetes under control after a stable insulin regimen were eligible to participate in this study;
6. Usage of systemic immune activation drugs (including but not limited to interferon or Interleukin-2) within 4 weeks prior to enrollment or within 5 half-lives of the drug (whichever is shorter);
7. Usage of systemic corticosteroids (\> 10 mg/d of prednisone equivalent) or other systemic immunosuppressive agents (including but not limited to prednisone, prednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor agents \[anti-TNF\]) within 2 weeks prior to enrollment. Local, ocular, intra-articular, nasal, and inhaled corticosteroids are permitted;
8. Patients requiring baseline and subsequent MRI tumor evaluation with previous allergic reactions to intravenous contrast agents may use preventive steroids;
9. Allowing the use of inhaled corticosteroids for chronic obstructive pulmonary disease, corticosteroid hydrochloride (e. g., fluorohydrocortisone) in patients with orthostatic hypotension, and low-dose corticosteroid maintenance for adrenal cortical insufficiency.
10. Patients with previous allogeneic bone marrow transplantation or previous solid organ transplantation.
11. Idiopathic pulmonary fibrosis, drug-induced pneumonia, mechanical pneumonia (i. e. bronchiolitis obliterans), history of idiopathic pneumonia or chest CT scan at screening showed evidence of active pneumonia.
12. Any live vaccine (e. g., vaccine against infectious diseases, such as influenza vaccine, varicella vaccine, etc.) within 4 weeks (28 days) before enrollment.13 Active infections, including tuberculosis (TB) (clinical diagnosis including clinical history, physical examination and imaging findings, and TB tests performed per local medical practice), hepatitis B {known HBV surface antigen (HBsAg) positive and HBVDNA 1000 cps / ml}, hepatitis C or human immunodeficiency virus (HIV antibody positive).
13. Patients with prior or cured HBV infection (defined as hepatitis B core antibody positive and HBsAg negative) were to be eligible to participate in the study only if HBVDNA was negative (HBVDNA˂ 1000 cps / ml);
14. Patients with positive hepatitis C (HCV) antibody are not eligible for the study only if polymerase chain reaction shows negative HCVRNA;
15. Clinically meaningful basic medicine, disease (e. g., dyspnea, pneumonia, pancreatitis, poorly controlled, poorly controlled diabetes, infection active or poorly controlled, or drug or alcohol abuse).
16. Presence of severe neurological or psychiatric disorders, including dementia and epileptic seizures.
17. The NCI-CTCAE grade 2 peripheral neuropathy.
18. Female patients during pregnancy or lactation.
19. Chronic bowel disease or short bowel syndrome.
20. Dihydropyrimidine dehydrogenase (DPD) enzyme deficiency.
21. Major cardiovascular diseases, such as New York Heart Association heart disease (grade II or higher), myocardial infarction within 3 months before randomization, unstable arrhythmia, or unstable angina pectoris.
22. Patients with known coronary artery disease, congestive heart failure not meeting the above criteria, or left ventricular ejection fraction \<50% must have an optimized stable medical regimen as determined by the treating physician, consulting a cardiologist if required.