Neoadjuvant Chemoradiotherapy Plus Tislelizumab Followed by TME for LARC.

Study Overview
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Brief Summary
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Long course radiotherapy plus neoadjuvant chemotherapy followed by resection total mesorecta excision has accepted widespread recognized in the treatment of locally advanced rectal cancer (LARC). Tislelizumab, an anti-PD1(programmed death 1) humanized IgG4 (Immunoglomin G4) monoclonal antibody, has been demonstrated with clinical activity and is approved for treating recurrent/refractory classical Hodgkin lymphoma and locally advanced/metastatic urothelial carcinoma in China. The aim of This NCRT-PD-1-LARC trial is to evaluate the efficacy and safety of long course neoadjuvant chemoradiotherapy plus tislelizumab followed by total mesorecta excision for LARC. This NCRT-PD-1-LARC trial will be a prospective, multicenter and phase Ⅱ clinical trial designed to evaluate the safety and efficacy of LARC patients treated with long course neoadjuvant chemoradiotherapy plus tislelizumab followed by total mesorecta excision. It will consecutively enroll 50 stage II/III LARC patients (cT3N0M0 and cT1-3N1-2M0) with the tumor distal location ≤ 10cm from anal verge at 7 centers in China. The enrolled patients will receive long course radiotherapy (50 Gy/25 f, 2 Gy/f, 5 days/week) and three 21-day cycles capecitabine (1000 mg/m2, bid, po, day1-14) plus three 21-day cycles tislelizumab (200 mg, iv.gtt, day8), followed by total mesorecta excision 6-12 week after the end of radiotherapy. The primary efficacy endpoint will be the pathological complete response (pCR) rate, which is defined as absence of viable tumor cells in the primary tumor and lymph nodes.

Official Title
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Rationale and Design of a Prospective, Multicenter Phase Ⅱ Clinical Trial of Safety and Efficacy Evaluation of Long Course Neoadjuvant Chemoradiotherapy Plus Tislelizumab Followed by TME for LARC.

Conditions
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Colorectal Neoplasms

Intervention / Treatment
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* Combination Product: long course radiotherapy + capecitabine + PD-1 monoclonal antibody treatment combinations


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Patients have been fully aware of the content of this study and signed the informed consent voluntarily; Patients with rectal cancers must satisfied all the following conditions: Stage II/III LARC (cT1-3N1-2M0)；Tumor distal location ≤10 cm from anal verge (MRI diagnosed); Patients regardless of gender with aged ≥18 years and ECOG score of 0 or 1; Physical and viscera function of patients can withstand major abdominal surgery; Patients are willing and able to follow the study protocol during the study; Patients give consent to the use of blood and pathological specimens for study; Within 28 days prior to enrolment, we must confirm a negative serological pregnancy test for child-bearing age women and they agree to use effective contraception for the duration of drug use and for 60 days after the last dose. Exclusion criteria: Patients have a present or previous active malignancy except the diagnosis of rectal cancer this time; Patients underwent major surgery within 4 weeks prior to study treatment; Patients have any condition affects the absorption of capecitabine through gastrointestinal tract; Patients have severe uncontrolled recurrent infections, or other severe uncontrolled concomitant diseases; Patients who are allergic to any of the ingredients under study; Patients with severe concomitant diseases with estimated survival ≤ 5 years; Patients with present or previous moderate or severe liver and kidney damage presently or previously; Patients have received other study medications or any immunotherapy currently or in the past; Patients preparing for or previously received organ or bone marrow transplant; Patients who received immunosuppressive or systemic hormone therapy for immunosuppressive purposes within 1 month prior to the initiation of study therapy; Patients with congenital or acquired immune deficiency (such as HIV infection); If patients with a history of uncontrolled epilepsy, central nervous system disease or mental disorder, the investigator will determine whether the clinical severity prevents the signing of informed consent or affects the patient's oral medication compliance; Patients with other factors that may affect the study results or cause the study to be terminated midway, such as alcoholism, drug abuse, other serious diseases (including mental illness) requiring combined treatment and severe laboratory examination abnormalities. Pregnant or lactating women

Ages Eligible for Study
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Minimum Age: 18 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: The enrolled patients in this NCRT-PD-1-LARC trial will receive long course radiotherapy (50 Gy/25 f, 2 Gy/f, 5 days/week) and three 21-day cycles capecitabine (1000 mg/m2, bid, po, day1-14) plus three 21-day cycles tislelizumab (200 mg, iv.gtt, day8), followed by total mesorecta excision 6-8 week after the end of radiotherapy.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: long course radiotherapy + capecitabine + PD-1 monoclonal antibody treatment combinations<br>long course radiotherapy + capecitabine + PD-1 monoclonal antibody treatment combinations in patients with locally advanced rectal cancer | Combination Product: long course radiotherapy + capecitabine + PD-1 monoclonal antibody treatment combinations<br>* long course radiotherapy + capecitabine + PD-1 monoclonal antibody treatment combinations in patients with locally advanced rectal cancer<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| pathologic complete response（pCR） | All the enrolled patients will receive total mesorectal excision (TME) 7-9 weeks after the end of long course radiotherapy. The rectal specimens will be evaluated by the pathologists who are experienced on the rectal cancer diagnosis according to the 1997 Dworak grading system. The rectal cancer will be classified into 5 grades. Grade 0-3 will be considered as non-pCR while grade 4 represent pCR. | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| neoadjuvant rectal (NAR) score | The neoadjuvant rectal (NAR) score is a promising indicator of survival after preoperative chemoradiotherapy for rectal cancer. The NAR score was calculated according to the following formula: NAR score = [5pN - 3(cT - pT) + 12]2∕9.61. (clinical tumor (cT) stage, pathologic tumor (pT) stage, pathologic nodal (pN) stage) | 1 year | 
| objective response rate (ORR) | ORR is evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. The ORR rate is the sum of complete response (CR) and partial response (PR) | 1 year | 
| R0 resection rate | During the surgical process, the surgeon will evaluate the level of cancer resection. It will be classified as R0, R1, R2 resection. Therefore, we can calculate R0 resection rate. | 1 year | 
| anal preservation rate | the surgeon will decide whether the anal can be preserved on the basis of the rectal cancer and intraoperative situation. anal preservation rate is the percentage of patients who achieve anal preservation. | 1 year | 
| 3-year local recurrence rate (LRR) | During the 3-year follow-up, the percentage of local recurrence. | 3 year | 
| 3-year disease free survival (DFS) | During the 3-year follow-up, the percentage of the patients who is disease free. | 3 year | 
| 3-year overall survival (OS) | During the 3-year follow-up, the percentage of the patients who is sill survival at the end of follow-up. | 3 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Colorectal Neoplasms, Programmed Cell Death 1 Receptor, Neoadjuvant Therapy