PACE: PD-1 Antibody For dMMR/MSI-H Stage III Colorectal Cancer

Study of Sintilimab vs Standard Therapy in Participants With Mismatch Repair Deficient (dMMR) or Microsatellite Instability-High (MSI-H) Stage III Colorectal Cancer

In this open-label phase III study, patients with local advanced colon cancer (TanyN+ ,M0, dMMR/MSI-H, at least 10cm from the anus verge)will be scheduled to Group A: receive anti-PD-1 antibody alone (8 cycles, 200mg iv drip Q3W) and Group B (4 or 8 cycles of XELOX: oxaliplatin 130mg/m2 day 1, capecitabine 2000mg/m2 days 1-14, repeated every 21 days). The primary endpoint was 3 Disease-free survival; analyses were done based on all patients with post-randomization data.

Study Overview

• Status: Recruiting
• Conditions: Colorectal Carcinoma
• Intervention / Treatment: Drug: Oxaliplatin; Drug: Sintilimab; Drug: capecitabine

• Study Type: Interventional
• Enrollment (Anticipated): 323
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Peirong Ding, professor; Phone Number: +86-13543478645; Email: dingpr@sysucc.org.cn
• Study Contact Backup: Name: Zhenlin Hou; Phone Number: +86-17612057762; Email: houzl@sysucc.org.cn

Study Locations

• China
  • Guangzhou, China
    • Recruiting
    • Sun Yat-sen University
    • Contact: Peirong Ding; Phone Number: +86-13543478645; Email: dingpr@sysucc.org.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Male or female subjects aged ≥18 years
2. ECOG PS 0/1
3. Histologically proven, stage III (i.e., any T, N1 or N2, M0) adenocarcinoma of the colon (as defined by the presence of the inferior pole of the tumour above the peritoneal reflection - that is, at least 10 cm from the anal margin).
4. Fully surgically resected tumour with clear resection margins (i.e., >1 mm)
5. Locally confirmed defective mismatch repair (dMMR) tumour (as defined by the lack of staining on either the pre-operative biopsy samples or resection specimens of at least one of the following proteins: MLH1 (mutL homolog 1), MSH2 (mutS homologue 2), MSH6 (mutS homolog 6), PMS2
6. Absence of metastases as shown by post-operative CT scan
7. Absence of major post-operative complications or other clinical conditions that, in the opinion of the investigator, would contraindicate adjuvant chemotherapy

Exclusion Criteria:

1. Rectal tumours (as defined by the presence of the inferior pole of the tumour below the peritoneal reflection - that is, <15 cm from the anal margin).
2. Inability to start adjuvant chemotherapy within 12 weeks after surgery
3. Administration of neoadjuvant systemic chemotherapy or radiotherapy before surgical resection of colon cancer
4. Prior organ transplantation, including allogeneic stem-cell transplantation

5. Significant acute or chronic infections including, among others:

   known history of testing positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) positive test for HBV (Hepatitis B) surface antigen or anti-HCV (Hepatitis C) antibody and confirmatory HCV RNA test

6. Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent:
7. Subjects with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible
8. Subjects requiring hormone replacement with corticosteroids are eligible if the steroids are administered only for the purpose of hormonal replacement and at doses ≤10 mg/day of prednisone or equivalent
9. Administration of steroids through a route known to result in a minimal systemic exposure (topical, intranasal, intro-ocular, or inhalation) are acceptable
10. Known severe hypersensitivity reactions to monoclonal antibodies (Grade ≥3 NCI-CTCAE v4.0), any history of anaphylaxis, or uncontrolled asthma (that is, 3 or more features of partially controlled asthma)
11. Persisting toxicity related to prior therapy of Grade >1 NCI-CTCAE v4.0; however, alopecia and sensory neuropathy Grade ≤2 is acceptable unless oxaliplatin administration is planned as part of the adjuvant treatment
12. Pregnancy or lactation
13. Known alcohol or drug abuse
14. Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (<6 months prior to enrollment), myocardial infarction (<6 months prior to enrollment), unstable angina, congestive heart failure (≥ New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication
15. Known history of colitis, pneumonitis and pulmonary fibrosis (for example, inflammatory bowel disease, uncontrolled asthma), which, in the opinion of the 16.Investigator, might impair the subject's tolerance of trial treatment.

Any psychiatric condition that would prohibit the understanding or rendering of informed consent 17.Other invasive malignancy within 2 years except for non-invasive malignancies such as cervical carcinoma in situ, non-melanomatous carcinoma of the skin or ductal carcinoma in situ of the breast that has/have been surgically cured.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sintilimab; Sintilimab 200mg iv drip Q3W for 8 courses	Drug: Sintilimab; Sintilimab 200mg iv drip Q3W
Experimental: XELOX; Patients receive chemotherapy comprising oxaliplatin 130mg/m² ivdrip over 2 hours on day 1,capecitabine 2000 mg/m² on days 1-14, treatment repeats every 21 days for 4 or 8 courses	Drug: Oxaliplatin; 130 mg/m² iv drip over 2 hours on day 1, repeated every 21 days.; Drug: capecitabine; 1000 mg/m² po twice daily on days 1- 14 repeated every 21 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease Free survival [ Time Frame: 3 years ]	Disease-free survival (DFS) at 3 years. DFS is measured from the date of randomisation to the date of first relapse (radiological or clinical) or death from any cause.	Up to 5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival [ Time Frame: 5 years ]	Overall survival (OS) at 5 years. OS is measured from the date of randomisation to date of death from any cause.	Up to 5 years

Collaborators and Investigators

• Sponsor: Sun Yat-sen University
• Collaborators: West China Hospital; Second Affiliated Hospital, School of Medicine, Zhejiang University

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2022
• Primary Completion (Anticipated): June 1, 2026
• Study Completion (Anticipated): December 31, 2028

Study Registration Dates

• First Submitted: January 19, 2022
• First Submitted That Met QC Criteria: February 2, 2022
• First Posted (Actual): February 11, 2022

Study Record Updates

• Last Update Posted (Actual): December 30, 2022
• Last Update Submitted That Met QC Criteria: December 29, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Keywords: dMMR/MSI-H
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Capecitabine; Oxaliplatin
• Other Study ID Numbers: B2021-361-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No