Pd1 Antibody Sintilimab ± Chemoradiotherapy for Locally Advanced Rectal Cancer

Study Overview
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Brief Summary
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In this study, participants with locally advanced rectal cancer patients will be treated according to MMR/MSI status. There will be two cohorts in this study: Cohort A and Cohort B. For Cohort A, dMMR or MSI-H patients will receive 4 cycles of neoadjuvant Pd1 antibody Sintilimab,followed by one of the following treatments: (1) surgery and adjuvant treatment, (2）another 4 cycles of sintilimab, followed by radical surgery or observation (only for cCR) . For Cohort B, pMMR/MSS/MSI-L patients will be randomized to receive neoadjuvant chemoradiotherapy ± four cycles of Pd1 antibody Sintilimab，followed by one of the following treatments: (1) curative surgery and four cycles of adjuvant chemotherapy;(2)four cycles of chemotherapy then observation (only cCR after neoadjuvant therapy)

Official Title
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Pd1 Antibody Sintilimab ± Chemoradiotherapy for Locally Advanced Rectal Cancer

Conditions
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Colorectal Cancer Stage II, Colorectal Cancer Stage III

Intervention / Treatment
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* Drug: Oxaliplatin
* Drug: Capecitabine
* Drug: Sintilimab
* Radiation: radiotherapy
* Procedure: total mesorectal excision
* Other: Watch and wait


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically proven colorectal adenocarcinoma; Cohort 1: Biopsy tissues with IHC indicates deficient mismatch repair(dMMR),that is,the loss of at least one of the four proteins ,MSH1,MSH2,MSH6,PMS2;or gene detection implies MSI-H; Cohort 2: Biopsy tissues with IHC indicates proficient mismatch repair(pMMR),that is positivity of all four proteins ,MSH1,MSH2,MSH6,PMS2;or gene detection implies MSS/MSI-L Clinical stage for rectal cancer patients is cT3-4N0M0 or cTxN+M0; Preoperative staging methods: all patients need to accept digital rectal examination(DRE).Patients with rectal cancer undergo high-resolution MRI±ultrasound colonoscopy/transrectal ultrasound for preoperative staging. Perienteric lymph nodes with short diameter ≥10mm or the shape of lymph nodes and its MRI characteristics are consistent with typical lymph node metastasis. If endoscopic ultrasonography is used in combination, and there is a contradiction between staging methods, the data should be submitted to the evaluation team of our center for the accurate staging; No symptoms of ileus; or ileus is alleviated after proximal colostomy. No rectal surgery except preventative stoma; No chemotherapy or radiotherapy; No biotherapy (e.g.monoclonal antibodies), immunotherapy (e.g.anti-PD-1 antibody,anti-PD-L1 antibody,anti-PD-L2 antibody or CTLA-4 antibody),or other clinical trials agents; No limit to previous endocrine therapy. Age between 18 and 75 years; ECOG performance status of 0 or 1; Life expectancy: more than 2 years; Hematopoietic: WBC>3×109/L;PLT>80×109/L; Hb>90g/L; Hepatic: ALT and AST<2 times upper limit of normal (ULN); bilirubin<1.5 times ULN; Renal: creatinine <1.5 times ULN or creatinine clearance ≥ 60 mL/min. Exclusion Criteria: Arrhythmias require antiarrhythmic therapy (with the exception of β-blockers or digoxin), symptomatic coronary artery disease or local myocardial ischemia (myocardial infarction within the past 6 months) or congestive heart failure exceeding NYHA II; Severe hypertension with poor control after medication; A known history of testing positive for HIV or chronic hepatitis B or C (high copy virus DNA) at active stage; Patients with active tuberculosis (TB) are receiving anti-tuberculosis treatment or have received anti-tuberculosis treatment within 1 year before screening; Other active severe clinical infections (NCI-CTC5.0); Apparent distant metastasis away from the pelvic before surgery; Cachexia, organ function decompensation; Previous pelvic or abdominal radiotherapy; Multiple primary colorectal cancers; Epilepsy require medical treatment (such as steroid or antiepileptic therapy); Other malignancy within the past 5 years with the exception of effectively treated carcinoma in situ of the cervix or basal cell carcinoma of the skin; Drug abuse and medical, psychological or social factors that may interfere with patients' participation in the study or affect the evaluation of the study; Patients have any active autoimmune diseases or a history of autoimmune diseases(including but not limited to: interstitial pneumonia, uveitis, enteritis, hepatitis, hypophysitis, nephritis, hyperthyroidism and decreased thyroid function; patients with vitiligo or with complete remission of asthma in childhood and without any intervention in adulthood may be included; patients with asthma requiring bronchodilators intervention are not included. Received any anti-infection vaccine (e.g. influenza vaccine, chickenpox vaccine, etc.) within 4 weeks before enrollment; Complications require long-term treatment with immunosuppressive drugs, or requiring systemic or local use of immunosuppressive corticosteroids(>10mg/day prednisone or other therapeutic hormones); Known or suspected allergy to the study drugs or to any drugs related to this trial; Any unstable condition or which endangers the patients' safety and compliance; Pregnant or breast-feeding women who are fertile without effective contraception; Refuse to sign the informed consent.

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A<br>After 4 cycles of neoadjuvant sintilimab treatment, the patients and doctors could choose one of the following treatments: (1) surgery, followed by 4 cycles of adjuvant sintilimab with or without Capeox chemotherapy; (2) another 4 cycles of sintilimab, followed by radical surgery or observation (only for patients with clinical complete response). | Drug: Oxaliplatin<br>* 130mg/m2, d1 q3w, in Capeox regimen (100mg/m2 when used cocurrently with radiotherapy), intravenous infusion<br>Drug: Capecitabine<br>* 1000mg/m2, bid, qd1-14, q3w, in Capeox regimen, oral administration<br>Drug: Sintilimab<br>* 200mg, d1 q3w, intravenous infusion<br>Procedure: total mesorectal excision<br>* total mesorectal excision after neoadjuvant treatment<br>Other: Watch and wait<br>* Watch and wait for cCR patients after neoadjuvant treatment<br>|
| Experimental: Cohort B-arm 1<br>After four cycles of neoadjuvant Sintilimab, Capeox and radiotherapy, the patients and doctors could choose one of the following treatments: (1) curative surgery and four cycles of adjuvant Capeox chemotherapy;(2)four cycles of Capeox chemotherapy then observation (only for patients with clinical complete response after neoadjuvant therapy) | Drug: Oxaliplatin<br>* 130mg/m2, d1 q3w, in Capeox regimen (100mg/m2 when used cocurrently with radiotherapy), intravenous infusion<br>Drug: Capecitabine<br>* 1000mg/m2, bid, qd1-14, q3w, in Capeox regimen, oral administration<br>Drug: Sintilimab<br>* 200mg, d1 q3w, intravenous infusion<br>Radiation: radiotherapy<br>* neoadjuvant radiotherapy with 50Gy to GTV, 45Gy to CTV in 25 fractions.<br>Procedure: total mesorectal excision<br>* total mesorectal excision after neoadjuvant treatment<br>Other: Watch and wait<br>* Watch and wait for cCR patients after neoadjuvant treatment<br>|
| Active Comparator: Cohort B-arm 2<br>After four cycles of neoadjuvant Capeox chemotherapy and radiotherapy, the patients and doctors could choose one of the following treatments: (1) curative surgery and four cycles of adjuvant Capeox chemotherapy;(2)four cycles of Capeox chemotherapy then observation (only for patients with clinical complete response after neoadjuvant therapy) | Drug: Oxaliplatin<br>* 130mg/m2, d1 q3w, in Capeox regimen (100mg/m2 when used cocurrently with radiotherapy), intravenous infusion<br>Drug: Capecitabine<br>* 1000mg/m2, bid, qd1-14, q3w, in Capeox regimen, oral administration<br>Radiation: radiotherapy<br>* neoadjuvant radiotherapy with 50Gy to GTV, 45Gy to CTV in 25 fractions.<br>Procedure: total mesorectal excision<br>* total mesorectal excision after neoadjuvant treatment<br>Other: Watch and wait<br>* Watch and wait for cCR patients after neoadjuvant treatment<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| complete response rate | the proportion of CR cases (pCR for those who underwent surgery and cCR for those who didn't receive surgery) | 6 weeks after curative surgery for pCR; 6 weeks after the completion of neoadjuvant therapy for cCR | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acute toxiticy according CTCAE5.0 | Acute toxiticy according CTCAE5.0 | From start of treatment to 3 months after the adjuvant therapy or last dose of treatment | 
| Tumor regresssion grade according to AJCC TRG grading system | Tumor regresssion grade according to AJCC TRG grading system | 6 weeks after curative surgery | 
| R0 resection rate | R0 resection rate | 6 weeks after curative surgery | 
| Local recurrence | Local recurrence | 5 years after curative surgery | 
| Distant metastasis | Distant metastasis | 5 years after curative surgery | 
| Tumor response | tumor volume reduction rate (TVRR) reaching 20% or above | 6 weeks after first study treatment |