Different Cycles of Preoperative Neoadjuvant Sintilimab in Mismatch-repair Deficient/microsatellite Instability-high, Locally Advanced Colorectal Cancer

Eight Vs Four Cycles of Preoperative Neoadjuvant Sintilimab in Mismatch-repair Deficient/microsatellite Instability-high, Locally Advanced Colorectal Cancer(OPEN): a Multi-center, Open-label, Prospective Randomized Controlled Trial

Colorectal cancer is one of the most common malignant tumors, accounting for approximately 10% of new cancer cases and cancer-related deaths worldwide each year. In recent years, with the development of industrialization and urbanization, the increase in the number of elderly patients, and changes in dietary structure and lifestyle habits, the incidence and mortality rates of colorectal cancer in China have risen significantly. Some patients are already in locally advanced or late stages at the time of diagnosis, making treatment more difficult. Among them, patients with MSI-H/dMMR colorectal cancer account for about 10% to 15% of the total.

Neoadjuvant therapy for rectal cancer primarily targets resectable mid-to-low rectal cancer patients with T3/4 and any N stage. Currently, neoadjuvant therapy for rectal cancer mainly involves chemoradiotherapy, while patients with a low risk of recurrence may opt for neoadjuvant chemotherapy. For patients with mid-to-low locally advanced rectal cancer, intensified systemic chemotherapy can be chosen before and after preoperative radiotherapy. For patients with technical difficulties in sphincter preservation but a strong desire to preserve the sphincter, higher intensity treatments can be considered, such as the CinClare protocol of concurrent chemoradiotherapy with capecitabine and irinotecan, the FOWARC protocol of concurrent radiotherapy with FOLFOX, or interval chemotherapy, including total neoadjuvant therapy. However, for MSI-H/dMMR patients, neoadjuvant chemoradiotherapy is less effective. Xu Ruihua from the Sun Yat-sen University Cancer Center evaluated the clinical response and safety of four cycles of neoadjuvant treatment with sintilimab in dMMR or MSI-H colorectal cancer. In this study, 16 patients underwent at least one response evaluation. All six patients who underwent radical surgery achieved R0 resection. Tumor shrinkage was observed in 15 patients (94%) at the first evaluation after treatment. Among the 16 evaluable patients, 3 (19%) underwent radical surgery and achieved pCR, 9 (56%) achieved cCR and opted for a watch-and-wait strategy, 3 (19%) did not achieve cCR and underwent radical surgery with residual tumor found in the pathological specimens. One patient (6%) discontinued treatment due to a severe adverse event (grade 3 encephalitis), did not achieve cCR, and refused surgery. The results of immunotherapy in patients with MSI-H/dMMR metastatic colorectal cancer have greatly encouraged researchers to explore its application in neoadjuvant therapy. The NICHE study, the world's first neoadjuvant immunotherapy study in non-metastatic colon cancer, showed a 100% MPR and a 69% pCR rate after neoadjuvant immunotherapy in 32 patients with dMMR colon cancer. Based on this study, the larger NICHE-2 study was conducted, enrolling a total of 112 patients with non-metastatic dMMR colon cancer. These patients received one dose of ipilimumab (1 mg/kg) combined with nivolumab (3 mg/kg) followed by one dose of nivolumab (3 mg/kg) monotherapy within 6 weeks before surgery. The short-term efficacy results showed an MPR of 95% and a pCR rate of 67%, consistent with previous results, with good tolerability and only 4% experiencing grade 3-4 adverse events.

Sintilimab targets the same molecule as nivolumab and pembrolizumab but has a different amino acid sequence. Multiple preclinical in vitro studies have validated the effect of sintilimab in blocking the PD-1 pathway. Completed preclinical pharmacodynamics, animal pharmacokinetics, and toxicology studies have shown that sintilimab has clear targets, reliable cell line sources, good drug stability, and has demonstrated good activity in completed preclinical studies.

Based on multiple previous studies, the optimal cycle for neoadjuvant immunotherapy has not yet been determined. However, different treatment cycles result in significant differences in pCR, which may be related to the number of treatment cycles. This study aims to explore the postoperative pathological complete response rate of 8 cycles versus 4 cycles of neoadjuvant sintilimab treatment in dMMR/MSI-H locally advanced colon cancer.

Study Overview

• Status: Recruiting
• Conditions: Colorectal Cancer
• Intervention / Treatment: Biological: Sintilimab

• Study Type: Interventional
• Enrollment (Estimated): 96
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Yugui Lian, M.D.; Phone Number: +86 0371-66279076; Email: fcclianyg@zzu.edu.cn

Study Locations

• China
  • Henan
    • Zheng'zhou, Henan, China, 450000
      • Recruiting
      • The First Affiliated Hospital of Zhengzhou University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• has pathologically confirmed colon cancer or upper rectal cancer (with the lower edge of the tumor more than 10 cm from the anal verge); clinical stage cT3/T4 or N+
• no urgent need for surgery due to bleeding, perforation, or obstruction
• immunohistochemistry of tumor biopsy indicating deficient mismatch repair (dMMR), defined by the loss of expression of one or more of the four proteins MSH1, MSH2, MSH6, and PMS2; or genetic testing indicating MSI-H

Exclusion Criteria:

• Has distant metastatic disease.
• Has received prior medical therapy (chemotherapy, immunotherapy, biologic, or targeted therapy), radiation therapy or surgery for management of colon cancer
• Has undergone any major surgical procedure, open biopsy, or experienced significant traumatic injury within 28 days prior to randomization
• Is receiving any other anticancer or experimental therapy. No other experimental therapies (including but not limited to chemotherapy, radiation, hormonal treatment, antibody therapy, immunotherapy, gene therapy, vaccine therapy, or other experimental drugs) of any kind are permitted while the participant is receiving study intervention
• There is a history of illness or evidence of disease, treatment, or abnormal laboratory test values that could potentially interfere with the trial results or hinder the subject's full participation in the study, or any other conditions deemed unsuitable for inclusion by the investigator.
• The investigator believes there are other potential risks that make the subject unsuitable for participation in this study.

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: 8 cycles of neoadjuvant treatment with Sintilimab; A total of 48 subjects were enrolled and received Sintilimab at a dose of 200 mg, administered via intravenous infusion on the first day of each cycle, with each cycle lasting 3 weeks (Q3W), for a total of 8 treatment cycles.	Biological: Sintilimab; Subjects were enrolled and received Sintilimab at a dose of 200 mg, administered via intravenous infusion on the first day of each cycle, with each cycle lasting 3 weeks (Q3W)
Active Comparator: 4 cycles of neoadjuvant treatment with Sintilimab; A total of 48 subjects were enrolled and received Sintilimab at a dose of 200 mg, administered via intravenous infusion on the first day of each cycle, with each cycle lasting 3 weeks (Q3W), for a total of 4 treatment cycles.	Biological: Sintilimab; Subjects were enrolled and received Sintilimab at a dose of 200 mg, administered via intravenous infusion on the first day of each cycle, with each cycle lasting 3 weeks (Q3W)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
the pathological complete response rate (pCR)	Evaluate the pathological complete response rate (pCR) after surgery in patients with locally advanced dMMR/MSI-H colorectal cancer who received 4 cycles versus 8 cycles of neoadjuvant treatment with sintilimab.	From randomization up to a median of 5 years after randomization.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants with treatment emergent adverse events (AEs), serious adverse events (SAEs), Immune-mediated Adverse Event (imAEs), AEs leading to death and AEs leading to discontinuation of study treatment		Up to approximately 5 years
Event-free Survival (EFS)	EFS is defined as the time from randomization to either disease recurrence or death due to any cause or treatment related toxicity that results in the participant not being suitable for surgery	From randomization up to a median of 5 years after randomization.
Overall Survival (OS)	OS is defined as time from randomization to death from any cause	From randomization up to a median of 5 years after randomization.

Collaborators and Investigators

• Sponsor: Yugui Lian

Study record dates

Study Major Dates

• Study Start (Actual): November 15, 2024
• Primary Completion (Estimated): November 15, 2027
• Study Completion (Estimated): November 15, 2031

Study Registration Dates

• First Submitted: November 9, 2024
• First Submitted That Met QC Criteria: November 20, 2024
• First Posted (Actual): November 21, 2024

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: March 11, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Site; Neoplasms; Intestinal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colonic Diseases; Genomic Instability; Colorectal Neoplasms; Microsatellite Instability
• Other Study ID Numbers: 2024-KY-1330-003

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Qualified researchers may request access to anonymized individual patient-level data (IPD) and related study documents of the eligible studies via the Data Sharing Portal.
• IPD Sharing Time Frame: Anonymized IPD will be made available within 6 months of publication of primary, key secondary and safety results for studies in product with approved indication(s) or terminated asset(s) across all indications.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No