Neoadjuvant Chemoradiotherapy Combined With PD-1 Inhibitor and Thymalfasin for pMMR/MSS Locally Advanced Mid-low Rectal Cancer

Study Overview
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Brief Summary
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This is an open, prospective, multi-center, single-arm phase II clinical study assessing the efficacy and safety of neoadjuvant chemoradiotherapy combined with PD-1 inhibitor and thymalfasin in patients with pMMR/MSS locally advanced middle and low rectal cancer.

Detailed Description
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This study is an open, prospective, multi-center, single-arm phase II clinical study. In this study, patients with pMMR/MSS locally advanced middle and low rectal cancer were selected as the subjects and treated with neoadjuvant treatment protocol of long-course concurrent chemoradiotherapy combined with PD-1 monoclonal antibody and thymalfasin. The primary endpoint of the study was pathological complete response (pCR) rate. The secondary study endpoints were neoadjuvant rectal (NAR) score, objective response rate (ORR), R0 resection rate, anal preservation rate, 3-year disease-free survival (DFS) rate, 3-year local recurrence-free survival (LRFS) rate, 3-year overall survival (OS) rate, tumor regression grade (TRG), safety and tolerability.

Official Title
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Efficacy and Safety of Neoadjuvant Chemoradiotherapy Combined With PD-1 Inhibitor and Thymalfasin in pMMR/MSS Locally Advanced Middle and Low Rectal Cancer: An Open, Multi-center, Prospective, Single-arm Phase II Clinical Study

Conditions
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Locally Advanced Rectal Cancer

Intervention / Treatment
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* Drug: capecitabine
* Drug: tislelizumab
* Drug: thymalfasin
* Radiation: long-term radiotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients who were fully informed of the study and voluntarily signed the informed consent form; Patients who were pathologically diagnosed with rectal adenocarcinoma via enteroscopic biopsy and met the following criteria: ①LARC at clinical stage II/III: cT1-4aN0-2M0; ② Distance between distal tumor and the anal verge ≤10 cm (measured by MRI); ③ No distant metastasis; ④ pMMR or MSS confirmed by immunohistochemistry or genetic test. Men and women aged ≥18 and ≤75 years old, with ECOG score of 0-1 points; Patients willing to accept the treatment protocol of neoadjuvant therapy + TME; Patients whose major organ functions met the following requirements (The values of laboratory tests within 14 days before enrollment must meet the following criteria): ① Blood routine test: (no blood transfusion or use of granulocyte colony-stimulating factor or drug correction within 14 days before screening): a) neutrophil count ≥1.5 × 109/L; b) platelet count ≥75 × 109/L; c) hemoglobin level ≥90 g/L ② Biochemical test: (no albumin infusion within 14 days prior to screening): a) serum creatinine ≤1.5 × upper limit of normal (ULN) or creatinine clearance >50 mL/min; b) serum total bilirubin ≤1.5 × ULN; c) aspartate aminotransferase (AST), alanine aminotransferase (ALT) ≤2.5 × ULN ③ Coagulation function: a) international normalized ratio (INR) ≤2.3 or prothrombin time (PT) ≤6 seconds longer than the range of normal control; ④ Normal thyroid function No immune system diseases (e.g., systemic lupus erythematosus, rheumatoid arthritis (RA), systemic vasculitis, scleroderma, mixed connective tissue disease, autoimmune hemolytic anemia, hyperthyroidism, hypothyroidism, and ulcerative colitis); Within 28 days before enrollment, women of childbearing age must have a negative serum pregnancy test and agree to take effective contraceptive measures during the use of investigational drug and within 60 days after the last drug administration. Female spouses of male subjects should also follow the above contraceptive requirements if they are of childbearing age; Patients whose body and organ functions can tolerate major abdominal surgery. Exclusion Criteria: Patients currently or previously with malignant tumors other than rectal cancer (except for cured basal cell carcinoma of skin or cervical carcinoma in situ); Patients treated with major surgery within 4 weeks before the start of research therapies; Patients with any condition that affected the absorption of capecitabine in the gastrointestinal tract; Patients with severe uncontrolled recurrent infections, or other severe uncontrolled concomitant diseases; Patients with severe diseases with an estimated survival of ≤5 years; Patients with congenital malformation, developmental disorder, genetic defect, or severe malnutrition; Patients who were ready to receive or had received organ or bone marrow transplantation; Pregnant or lactating women; Patients with severe cardiovascular disease, hepatic or renal disease, respiratory disease, uncontrolled hypertension (systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg), diabetic complication, various acute diseases or acute stage of chronic diseases; Patients diagnosed with congenital or acquired immune deficiency (such as HIV infection), lymphoma, leukemia, or other autoimmune diseases, or those suffering active tuberculosis or receiving anti-tuberculous therapy; Patients who received immunotherapy within 3 months before screening, such as long-term treatment with prednisone at a dose >10 mg/day or corticosteroid at an equivalent dose (more than 14 consecutive days through oral administration or infusion), or immunosuppressant; Patients who received blood or blood-related products, including immunoglobulin, within 3 months, or those who planned to use them at the beginning of the study; Patients treated with other investigational drugs within 1 month before screening; Patients with a history of allergy or intolerance to any investigational drug or its components; Patients with suspected or known alcohol or drug dependence; Patients with dMMR or MSI-H confirmed by immunohistochemistry or genetic test; Patients with T4b or MRF(+) according to baseline rectal MRI; Patients with other conditions unsuitable for this clinical trial judged by the investigator.

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
Interventional Model Description: neoadjuvant chemoradiotherapy combined with PD-1 monoclonal antibody and thymalfasin
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: cCRT+tislelizumab+thymalfasin<br>A total of 20 pMMR/MSS locally advanced middle and low rectal cancer patients will receive long-course concurrent chemoradiotherapy combined with 3 cycles of tislelizumab and 11 weeks of thymalfasin therapy. | Drug: capecitabine<br>* 825-1000mg/m2,po,bid<br>Drug: tislelizumab<br>* 200mg,iv.gtt,q3w<br>Drug: thymalfasin<br>* 4.8mg,sc,biw<br>Radiation: long-term radiotherapy<br>* 50 Gy/25 f, 2 Gy/day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| pCR rate | pathological complete response rate | within 10 days after surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ORR | objective response rate; The ORR rate is the result of complete response (CR) rate plus partial response (PR) rate. | before surgery | 
| 3-y DFS rate | 3-year disease free survival rate | 3 years | 
| 3-y LRFS rate | 3-year local recurrence free survival rate | 3 years | 
| 3-y OS rate | 3-year overall survival rate | 3 years | 
| TRG | Tumor regression grade | within 10 days after surgery | 
| R0 resection rate | rate of R0 resection | within 10 days after surgery | 
| anal preservation rate | proportion of patients with preserved anal sphincter | instantly after surgery | 
| NAR score | neoadjuvant rectal score | within 10 days after surgery | 
| incidence of surgical complications | incidence of surgical complications within 30 days after surgery | within 30 days after surgery | 
| TRAE | incidence of treatment-related adverse event | from commencing of treatment to the 30th day after surgery | 
| irAE | incidence of immune-related adverse event | from commencing of PD-1 inhibition to the 30th day after surgery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pMMR/MSS, locally Advanced Rectal Cancer, PD-1, neoadjuvant, chemoradiation, Thymalfasin