Serplulimab Combined With CAPEOX + Celecoxib as Neoadjuvant Treatment for Locally Advanced Rectal Cancer

Study Overview
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Brief Summary
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Colorectal cancer of Mismatch Repair-proficient (pMMR)/ Microsatellite Stability (MSS) accounts for approximately 85% of all colorectal cancer patients, which might be insensitive to immunotherapy. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Chemotherapy, such as CAPEOX regimen, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Celecoxib, a COX-2 inhibitor, can improve the immune microenvironment and have a potential to synergy with immunotherapy. Chemotherapy can improve the immunogenicity of cancer cells that might enhance the efficacy of immunotherapy. The aim of this study is to explore whether chemotherapy and cyclooxygenase (COX) inhibitors combined with anti-PD-1 monoclonal antibody (mAb) could improve efficacy for resectable colorectal cancer patient with the pMMR/MSS phenotype.

Official Title
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A Phase II Study to Explore the Neoadjuvant Treatment of Serplulimab Combined With CAPEOX + Celecoxib in the Treatment of Locally Advanced Rectal Cancer

Conditions
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pMMR, MSS, MSI-L, Locally Advanced Rectal Carcinoma

Intervention / Treatment
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* Drug: Serplilumab
* Drug: Capecitabine
* Drug: Oxaliplatin
* Drug: Celecoxib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing and able to provide written informed consent. Male or female subjects ≧ 18 years ≦ 75 of age. Histological or cytological documentation of adenocarcinoma of the rectum. No previous any systemic anticancer therapy for rectal cancer disease. The lower margin of the tumor is less than 10cm from the anus verge. cT3N1M0, T4N0-1M0 MSS. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. At least one measurable lesion was evaluated according to RECIST 1.1. Eligible tumor tissues were identified for MSI/MMR assays. Expected survival of at least 3 months. Hepatitis B Surface Antigen (HBsAg) (-) and Hepatitis B Core Antibody (HBcAb) (-). If HBsAg (+) or HBcAb (+), HBV-DNA must be less than 2500 copies/mL or 500 IU/mL to be enrolled. Patients with HCV antibody (-) or HCV-RNA negative can be enrolled. Aspartate aminotransferase (AST) must be ≤ 3 x ULN for the lab. If HCV-RNA is positive, patients with both alanine aminotransferase (ALT) and aspartate aminotransferase (AST) performed ≤3×ULN could be enrolled. Patients infected with both hepatitis B virus and hepatitis C virus should be excluded (positive for HBsAg or HBcAb and positive for HCV antibodies). Exclusion Criteria: Patients with recurrent rectal cancer or a history of pelvic radiotherapy. Patients with a history of inflammatory bowel disease. Patients with acquired immunodeficiency syndrome (AIDS-related illnesses) or known human immunodeficiency virus (HIV) disease (HIV1 antibody, HIV2 antibody, HTLV1 antibody positive) should be excluded. Patients who are preparing for or have previously received an organ or bone marrow transplant. History of myocardial infarction, poorly controlled arrhythmias (including QTc interval ≥470 ms in women) in the 6 months prior to randomization (QTc interval calculated by Fridericia formula). According to New York College of Cardiology (NYHA) standards for Grade III-IV cardiac insufficiency or cardiac color ultrasound: left ventricular ejection fraction (LVEF) <50%.Poor hypertension control (systolic blood pressure ≥150 mmHg and/or diastolic blood pressure ≥100 mmHg), a past hypertensive crisis or hypertensive encephalopathy. Patients with active tuberculosis. The patients had previously been treated with other antibodies/drugs that target immune checkpoints, such as PD-1, PD-L1, and cytotoxic T lymphocyte-associated Antigen 4 (CTLA-4). Patients are participating in other clinical studies, or plan to start this study treatment less than 14 days from the end of the previous clinical study. Uncontrolled tumor-related pain. 11.A known history of severe allergy to any monoclonal antibody. 12.Known to be allergic to any oxaliplatin and capecitabine ingredients. 13.Pregnant or lactating women. 14.The investigators determined that the patient had other factors that might have led to the early termination of the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Serplulimab+CAPEOX+celecoxib<br>articipants will receive serplulimab 300 mg every 3 weeks (Q3W) concurrently with CAPEOX regimen: Oxaliplatin(130mg/m2) on day 1 of each cycle and Capecitabine, 1000mg/m2, PO, BID, day1-14, q3w and celecoxib, 200mg, PO, BID, day1-21, q3w. Treatment repeats every 3 weeks for 6-8 cycles followed by surgery (total mesorectal excision, TME). | Drug: Serplilumab<br>* Serplilumab is an innovative monoclonal antibody targeting PD-1, developed by Shanghai Henlius Biotech, Inc. 300 mg, q3w<br>* Other names: HLX10;Drug: Capecitabine<br>* Given PO<br>* Other names: Xeloda;Drug: Oxaliplatin<br>* Given IV<br>* Other names: OHP;Drug: Celecoxib<br>* celebrex<br>* Other names: Given PO;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathological complete response rates | Proportion of patients experiencing a pCR to perioperative PD-1 antibody | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Major pathological response rates | The proportion of patients experiencing a major pathological response to perioperative PD-1 antibody | 1 year | 
| Rate of clinical complete response rate (cCR) | Proportion of patients experiencing a cCR to perioperative PD-1 antibody | 1 year | 
| R0 resection rates | The proportion of patients achieved a complete resection with negative margin | 1 year | 
| Treatment-related adverse events. | Assessed by evaluation of treatment-related adverse events. | 1 year | 
| Detection of MRD | To detect ctDNA in peripheral blood before and after treatment | 1year | 
| single cell sequence | Use single cell sequence to describe changes in the microenvironment of rectal cancer before and after treatment | 1year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CAPEOX, Rectal cancer, Serplulimab, Celecoxib, neoadjuvant therapy