Pd1 Antibody Sintilimab ± Chemoradiotherapy for Locally Advanced Rectal Cancer

• Sponsor: Sun Yat-sen University (Other)
• Overall Status: Recruiting
• CT.gov ID: NCT04304209
• Collaborator: (none)
• Enrollment: 195
• Location: 1
• Arms: 3
• Anticipated Duration (Months): 84
• Patients Per Site Per Month: 2.3

Study Details

Study Description

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 neoadjuvant Pd1 antibody Sintilimab and surgery or watch and wait, followed by adjuvant treatment. For Cohort B, pMMR/MSS/MSI-L patients will be randomized to receive neoadjuvant chemoradiotherapy ± Pd1 antibody Sintilimab， followed by surgery or watch and wait, and adjuvant treatment.

Condition or Disease	Intervention/Treatment	Phase
Colorectal Cancer Stage II; Colorectal Cancer Stage III; Mmr Deficiency; MSI-H	Drug: Oxaliplatin; Drug: Capecitabine; Drug: Sintilimab; Radiation: radiotherapy; Procedure: total mesorectal excision; Other: Watch and wait	Phase 2/Phase 3

Study Design

• Study Type: Interventional
• Anticipated Enrollment: 195 participants
• Allocation: Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Pd1 Antibody Sintilimab ± Chemoradiotherapy for Locally Advanced Rectal Cancer
• Actual Study Start Date: Oct 18, 2019
• Anticipated Primary Completion Date: Oct 18, 2021
• Anticipated Study Completion Date: Oct 18, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort A Four cycles of neoadjuvant PD1 antibody Sintilimab, followed by curative surgery or watch and wait, then four cycles of adjuvant PD1 antibody Sintilimab ± Capeox according to pathologic response	Drug: Oxaliplatin; 130mg/m2, d1 q3w, in Capeox regimen (100mg/m2 when used cocurrently with radiotherapy), intravenous infusion; Drug: Capecitabine; 1000mg/m2, bid, qd1-14, q3w, in Capeox regimen, oral administration; Drug: Sintilimab; 200mg, d1 q3w, intravenous infusion; Procedure: total mesorectal excision; total mesorectal excision after neoadjuvant treatment; Other: Watch and wait; Watch and wait for cCR patients after neoadjuvant treatment
Experimental: Cohort B-arm 1 Four cycles of neoadjuvant PD1 antibody Sintilimab, Capeox chemotherapy and concurrent radiotherapy, followed by curative surgery or watch and wait, then four cycles of adjuvant Capeox chemotherapy	Drug: Oxaliplatin; 130mg/m2, d1 q3w, in Capeox regimen (100mg/m2 when used cocurrently with radiotherapy), intravenous infusion; Drug: Capecitabine; 1000mg/m2, bid, qd1-14, q3w, in Capeox regimen, oral administration; Drug: Sintilimab; 200mg, d1 q3w, intravenous infusion; Radiation: radiotherapy; neoadjuvant radiotherapy with 50Gy to GTV, 45Gy to CTV in 25 fractions.; Procedure: total mesorectal excision; total mesorectal excision after neoadjuvant treatment; Other: Watch and wait; Watch and wait for cCR patients after neoadjuvant treatment
Active Comparator: Cohort B-arm 2 Four cycles of neoadjuvant Capeox chemotherapy and concurrent radiotherapy, followed by curative surgery or watch and wait, then four cycles of adjuvant Capeox chemotherapy	Drug: Oxaliplatin; 130mg/m2, d1 q3w, in Capeox regimen (100mg/m2 when used cocurrently with radiotherapy), intravenous infusion; Drug: Capecitabine; 1000mg/m2, bid, qd1-14, q3w, in Capeox regimen, oral administration; Radiation: radiotherapy; neoadjuvant radiotherapy with 50Gy to GTV, 45Gy to CTV in 25 fractions.; Procedure: total mesorectal excision; total mesorectal excision after neoadjuvant treatment; Other: Watch and wait; Watch and wait for cCR patients after neoadjuvant treatment

Outcome Measures

Primary Outcome Measures

1. Pathologic complete response rate [6 weeks after curative surgery]

   Pathologic complete response rate

Secondary Outcome Measures

1. Acute toxiticy according CTCAE5.0 [From start of treatment to 3 months after the adjuvant chemotherapy]

   Acute toxiticy according CTCAE5.0

2. Tumor regresssion grade according to AJCC TRG grading system [6 weeks after curative surgery]

   Tumor regresssion grade according to AJCC TRG grading system

3. R0 resection rate [6 weeks after curative surgery]

   R0 resection rate

4. Local recurrence [5 years after curative surgery]

   Local recurrence

5. Distant metastasis [5 years after curative surgery]

   Distant metastasis

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Medical Oncology,Sun Yat-sen University Cancer Center	Guangzhou	Guangdong	China	510060

Sponsors and Collaborators

• Sun Yat-sen University

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

• Allegra CJ, Yothers G, O'Connell MJ, Beart RW, Wozniak TF, Pitot HC, Shields AF, Landry JC, Ryan DP, Arora A, Evans LS, Bahary N, Soori G, Eakle JF, Robertson JM, Moore DF Jr, Mullane MR, Marchello BT, Ward PJ, Sharif S, Roh MS, Wolmark N. Neoadjuvant 5-FU or Capecitabine Plus Radiation With or Without Oxaliplatin in Rectal Cancer Patients: A Phase III Randomized Clinical Trial. J Natl Cancer Inst. 2015 Sep 14;107(11). pii: djv248. doi: 10.1093/jnci/djv248. Print 2015 Nov. Erratum in: J Natl Cancer Inst. 2016 Apr;108(4). pii: djw057. doi: 10.1093/jnci/djw057. Erratum in: J Natl Cancer Inst. 2018 Jul 1;110(7):794.
• Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, Skora AD, Luber BS, Azad NS, Laheru D, Biedrzycki B, Donehower RC, Zaheer A, Fisher GA, Crocenzi TS, Lee JJ, Duffy SM, Goldberg RM, de la Chapelle A, Koshiji M, Bhaijee F, Huebner T, Hruban RH, Wood LD, Cuka N, Pardoll DM, Papadopoulos N, Kinzler KW, Zhou S, Cornish TC, Taube JM, Anders RA, Eshleman JR, Vogelstein B, Diaz LA Jr. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med. 2015 Jun 25;372(26):2509-20. doi: 10.1056/NEJMoa1500596. Epub 2015 May 30.

• Responsible Party: Ruihua Xu, Professor, Sun Yat-sen University
• ClinicalTrials.gov Identifier: NCT04304209
• Other Study ID Numbers: B2019-149
• First Posted: Mar 11, 2020
• Last Update Posted: Mar 12, 2020
• Last Verified: Mar 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Colorectal Neoplasms; Capecitabine; Oxaliplatin

Study Results

No Results Posted as of Mar 12, 2020