Nodes-sparing Short-course Radiation Combined With CAPOX and Tislelizumab for MSS Middle and Low Rectal Cancer

Study Overview
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Brief Summary
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This is an open-label, prospective, multicenter phase II clinical trial to evaluate modified short-course radiation (Radiation targeting the tumor bed without irradiating surrounding tumor-draining lymph nodes) combined with CAPOX and PD-1 Inhibitor (Tislelizumab) for patients with MSS middle and low rectal cancer. A total of 32 patients will be enrolled in this trial. The primary endpoint is the rate of pathological complete response (pCR). The organ preservation rate, tumor regression grade, long-term prognosis, and adverse effects will also be analyzed.

Official Title
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Modified Short-Course Radiation Combined With CAPOX and Tislelizumab for MSS Locally Advanced of Middle and Low Rectal Cancer (mRCAT): An Open-label, Single-arm, Prospective Multicenter Clinical Trial

Conditions
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Low Rectal Cancer

Intervention / Treatment
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* Radiation: Modified short-course radiotherapy
* Drug: PD-1 antibody
* Drug: Capecitabine
* Drug: Oxaliplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients who have a strong willingness to preserve the anus and are willing to receive neoadjuvant therapy. Male or Female aged 18-75. Patients diagnosed with low rectal cancer within 10 cm from the lower edge of the tumor to the anal verge by pelvic MRI and anorectoscopy, the clinical stage is cT2N+M0/cT3-4aN0/+M0, the lymph nodes are limited to the mesorectum, the circumferential resection margin is negative, tumor occupies <2/3 circle of bowel lumen. Histologically confirmed rectal adenocarcinoma; Genetic testing suggests MSI-L or MSS, or tumor biopsy immunohistochemistry reveals pMMR, that is, MSH1, MSH2, MSH6, and PMS2 are all positive. Eastern Cooperative Oncology Group (ECOG) 0-1. No previous treatment(including anti-tumor therapy、immunotherapy or pelvic radiation). Adequate hematologic, hepatic, renal, thyroid and cardiac function: white blood cells ≥3500/mm3, neutrophils ≥1800/mm3, platelets ≥100,000/mm3, hemoglobin ≥100 g/L; activated partial thromboplastin time, prothrombin time and international normalized ratio ≤1.5 × ULN; aspartate aminotransferase and alanine aminotransferase ≤3.0 × upper limit of normal (ULN), bilirubin ≤1.25 × ULN, serum albumin ≥28 g/L. creatinine clearance ≥50 mL/mi, creatinine ≤1.5 × ULN; Informed consent form signed. Exclusion Criteria: Patients with a previous history of malignant tumors besides rectal cancer. Patients with distant metastases before enrollment. Patients with positive internal or external iliac lymph nodes are assessed by MRI or CT. Patients with obstruction, perforation, or bleeding that require emergency surgery. Patients with severe concomitant diseases and estimated survival time ≤ 5 years. Allergic to any component of the therapy. Patients with poorly differentiated adenocarcinoma, signet ring cell carcinoma, or mucinous adenocarcinoma. Patients who received immunosuppressive or systemic hormone therapy for immunosuppressive purposes within 1 month prior to the initiation of therapy. Patients who have received any other experimental drug (including immunotherapy) or participated in another interventional clinical trial within 30 days before screening. Factors leading to study termination, such as alcoholism, drug abuse, other serious illnesses (including psychiatric disorders) requiring combination therapy, and patients with severe laboratory abnormalities. Patients with congenital or acquired immune deficiency (such as HIV infection). Vulnerable groups, including mentally ill, cognitively impaired, critically ill patients, minors, pregnant or lactating women, illiterate, etc. Other conditions that investigators consider not suitable for this 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: Treatment Arm<br>Participants will receive 5*5Gy modified short-course radiation (radiation targeting the tumor bed without irradiating surrounding tumor-draining lymph nodes) concurrently with CAPOX and tislelizumab regimens: Oxaliplatin, 130mg/m2, intravenous infusion,d1 of each cycle; Capecitabine, 1000mg/m2, PO, BID, d1-14 and tislelizumab, 200mg intravenous infusion d1 of each cycle. CAPOX and tislelizumab repeat every 3 weeks for 3 cycles, followed by total mesorectal excision surgery. | Radiation: Modified short-course radiotherapy<br>* radiation targeting the tumor bed without irradiating surrounding tumor-draining lymph nodes: 25Gy/5Fx<br>Drug: PD-1 antibody<br>* PD-1 antibody (Tislelizumab): 200mg d1 q3w<br>Drug: Capecitabine<br>* Capecitabine: 1000mg/m2 d1-14 q3w<br>Drug: Oxaliplatin<br>* Oxaliplatin: 130mg/m2 d1 q3w<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathological complete response (pCR) rate | The status of pCR will be evaluated after the TME surgery. | within 10 days after surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor regression grade | TRG is evaluated according to the AJCC system. TRG0-1 is defined as good response, TRG2 as moderate response, and TRG3 as poor response. | within 10 days after surgery | 
| Local recurrence rate(LRR) | Presence of adenocarcinoma within the rectal wall or within the mesorectum confirmed by pathology. | 3 years after sugery | 
| Disease free survival(DFS) | The three-year disease-free survival of patients. | 3 years after surgery | 
| Overall survival(OS) | The three-year overall survival of patients. | 3 years after surgery | 
| Adverse effects rate | Rate of radiotherapy, chemotherapy and immunotherapy related adverse events | From date of initiation of treatment until the date of death from any cause, assessed up to 5 years | 
| Rectal specific quality of life assessment via QLQ-CR29 | Rectal specific quality of life according to European Organization for Research and Treatment of Cancer ( EORTC) Quality of life questionnaire QLQ-CR29. scale from 0 to 100, A higher scale represents better function and a higher quality of life. | Baseline and months 3, 6, 12, 24, 36, 60 after the surgery | 
| Quality of life assessment via QLQ-C30 | Quality of life according to EORTC Quality of life Questionnaire QLQ-C30 version 3.0. Score range from 0 to 100 points. A higher score represents better function and a higher quality of life. | Baseline and months 3, 6, 12, 24, 36, 60 after the surgery | 
| Validation of the Wexner score | The change of severity of fecal incontinence assessment according to Wexner score. a score from 0-20, where 0 is perfect continence and 20 is complete incontinence. | Months 3, 6, 12, 24, 36, 60 after the surgery |