Pd1 Antibody Sintilimab ± Chemoradiotherapy for Locally Advanced Rectal Cancer

Phase 2

Active, not recruiting

• Conditions: Colorectal Cancer Stage II; Colorectal Cancer Stage III
• Interventions: Drug: Oxaliplatin; Drug: Capecitabine; Drug: Sintilimab; Procedure: total mesorectal excision; Radiation: radiotherapy; Other: Watch and wait

• Registration Number: NCT04304209
• Lead Sponsor: Sun Yat-sen University

Brief Summary

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)

Detailed Description

Not available

Study Timeline

• Study Start: 2019-10-28
• Study First Submitted: 2020-03-09
• Study First Submitted QC: 2020-03-09
• Study First Posted: 2020-03-11
• Status Verified: 2023-01
• Last Update Submitted: 2023-01-29
• Last Update Posted: 2023-02-01
• Primary Completion: 2026-10-18
• Study Completion: 2026-10-18

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 195

Inclusion Criteria

1. Histologically proven colorectal adenocarcinoma;
2. 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
3. Clinical stage for rectal cancer patients is cT3-4N0M0 or cTxN+M0;
4. 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;
5. No symptoms of ileus; or ileus is alleviated after proximal colostomy.
6. No rectal surgery except preventative stoma;
7. No chemotherapy or radiotherapy;
8. 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;
9. No limit to previous endocrine therapy.
10. Age between 18 and 75 years;
11. ECOG performance status of 0 or 1;
12. Life expectancy: more than 2 years;
13. Hematopoietic: WBC>3×109/L;PLT>80×109/L; Hb>90g/L;
14. Hepatic: ALT and AST<2 times upper limit of normal (ULN); bilirubin<1.5 times ULN;
15. Renal: creatinine <1.5 times ULN or creatinine clearance ≥ 60 mL/min.

Exclusion Criteria

1. 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;
2. Severe hypertension with poor control after medication;
3. A known history of testing positive for HIV or chronic hepatitis B or C (high copy virus DNA) at active stage;
4. Patients with active tuberculosis (TB) are receiving anti-tuberculosis treatment or have received anti-tuberculosis treatment within 1 year before screening;
5. Other active severe clinical infections (NCI-CTC5.0);
6. Apparent distant metastasis away from the pelvic before surgery;
7. Cachexia, organ function decompensation;
8. Previous pelvic or abdominal radiotherapy;
9. Multiple primary colorectal cancers;
10. Epilepsy require medical treatment (such as steroid or antiepileptic therapy);
11. 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;
12. Drug abuse and medical, psychological or social factors that may interfere with patients' participation in the study or affect the evaluation of the study;
13. 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.
14. Received any anti-infection vaccine (e.g. influenza vaccine, chickenpox vaccine, etc.) within 4 weeks before enrollment;
15. Complications require long-term treatment with immunosuppressive drugs, or requiring systemic or local use of immunosuppressive corticosteroids(>10mg/day prednisone or other therapeutic hormones);
16. Known or suspected allergy to the study drugs or to any drugs related to this trial;
17. Any unstable condition or which endangers the patients' safety and compliance;
18. Pregnant or breast-feeding women who are fertile without effective contraception;
19. Refuse to sign the informed consent.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cohort A	Watch and wait	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).
Cohort A	total mesorectal excision	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).
Cohort B-arm 1	radiotherapy	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)
Cohort B-arm 1	total mesorectal excision	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)
Cohort B-arm 1	Watch and wait	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)
Cohort B-arm 2	radiotherapy	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)
Cohort B-arm 2	total mesorectal excision	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)
Cohort B-arm 2	Watch and wait	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)
Cohort A	Oxaliplatin	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).
Cohort A	Capecitabine	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).
Cohort A	Sintilimab	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).
Cohort B-arm 1	Capecitabine	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)
Cohort B-arm 1	Sintilimab	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)
Cohort B-arm 1	Oxaliplatin	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)
Cohort B-arm 2	Oxaliplatin	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)
Cohort B-arm 2	Capecitabine	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)

Primary Outcome Measures

Name	Time	Method
complete response rate	6 weeks after curative surgery for pCR; 6 weeks after the completion of neoadjuvant therapy for cCR	the proportion of CR cases (pCR for those who underwent surgery and cCR for those who didn't receive surgery)

Secondary Outcome Measures

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

Trial Locations

Locations (1)

Medical Oncology,Sun Yat-sen University Cancer Center; 🇨🇳 Guangzhou, Guangdong, China