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)

Phase 3

Not yet recruiting

• Conditions: Rectal Cancer
• Interventions: Drug: AK104 plus; Drug: Chemo only

• Registration Number: NCT06832917
• Lead Sponsor: Wan He

Brief Summary

The goal of this clinical trial is to learn if neoadjuvant short-course radiation (SCRT) followed by 6 cycles of cadonilimab plus mFOLFOX6 works to treat patients with locally advanced rectal cancer (LARC). It will also learn about the safety of the combined regimen. The main questions it aims to answer are:

Does the neoadjuvant SCRT plus dual immunotherapy and chemotherapy can improve pathological complete response(pCR) rate? What medical problems do participants have when receiving chemotherapy plus cadonilimab compared to chemotherapy only?

Participants will:

Receiving cadonilimab plus mFOLFOX6 or mFOLFOX6 every 2 weeks for 3 months Visit the clinic once every 2 weeks for checkups and tests

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2025-02-13
• Study First Submitted QC: 2025-02-13
• Study First Posted: 2025-02-18
• Status Verified: 2025-03
• Last Update Submitted: 2025-03-09
• Last Update Posted: 2025-03-11
• Study Start: 2025-03-31
• Primary Completion: 2028-12-31
• Study Completion: 2029-12-31

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 238

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 PET / CT, staging criteria per AJCC 8th edition cancer stage, cT 3-T4 / N + M0.

  2. 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.

  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 activated partial 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-Gault formula)

Exclusion Criteria

• 1. Previous history of severe hypersensitivity to other monoclonal antibodies or any component of AK 104.

  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).

  3. Previous treatment against the PD-1 receptor or its ligand PD-L1 or the cytotoxic 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, 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 glomerulnephritis; 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. Receiving systemic immune stimulation drugs (including but not limited to interferon or IL-2) within 4 weeks prior to enrollment or within 5 half-lives of the drug (whichever is shorter); 7. Received 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-TNF agents [anti-TNF]) within 2 weeks prior to enrollment. Local, ocular, intra-articular, nasal, and inhaled corticosteroids are permittedt; 8. Patients requiring baseline and subsequent MRI tumor evaluation with previous allergic reactions to intravenous contrast agents may use preventive steroids.

  5. Allowing the use of inhaled corticosteroids for chronic obstructive pulmonary disease, corticosteroid hydrochloride (e. g., flurohydrocortisone) in patients with orthostatic hypotension, and low-dose corticosteroid maintenance for adrenal cortical insufficiency.

  6. Patients with previous allogeneic bone marrow transplantation or previous solid organ transplantation.

  7. 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.

  8. 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 (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).

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

  10. Patients with positive hepatitis C (HCV) antibody are not eligible for the study 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 active or poorly controlled, or drug or alcohol abuse).

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

  13. He had an 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.

  14. 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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
AK104 plus	AK104 plus	SCRT followed by AK104 plus chemotherapy
AK104 plus	Chemo only	SCRT followed by AK104 plus chemotherapy
Chemo only	Chemo only	SCRT followed by chemotherapy

Primary Outcome Measures

Name	Time	Method
3-year disease free survival (3-y DFS)	3-year	The survival rate of patients without disease recurrence or death due to the disease progression patients at 36 months.

Secondary Outcome Measures

Name	Time	Method
Pathological complete response rate	Up to 6 months	The proportion of patients with no tumor cells in the postoperative specimens
Overall Survival	Up to 5 years	Time from the date of randomization until the date of death from any cause.
Objective Response Rate	Up to 6 months	The rate of participants that achieve either a complete response (CR) or a partial response (PR).
Clinical complete response rate	Up to 36 months	The disappearance of all detectable clinical and imaging evidence of a tumor after treatment
Incidence of adverse events	Up to 36 months	Number of patients with AE, treatment-related AE (TRAE), immune-related AE (irAE), AE of special interest (AESI), serious adverse event (SAE) assessed by CTCAE v5.0.