Adjuvant PD-1 Blockade for High-risk Stage-II DMMR/MSI-H Colorectal Cancer
- Conditions
- Microsatellite Instability HighColorectal Cancer
- Interventions
- Drug: Adjuvant chemotherapy
- Registration Number
- NCT06520683
- Lead Sponsor
- Sun Yat-sen University
- Brief Summary
This open-label phase III trial investigates the efficacy of two cycles of PD-1 blockade (Tislelizumab) as adjuvant therapy to see how it works compared with standard of care (SOC) in treating patients with stage II dMMR/MSI-H colorectal cancer.
The rational of giving PD-1 blockade as adjuvant therapy is based on the fact that tumor recurrence is extremely low among patients receiving neoadjuvant immunotherapy, which suggests that PD-1 blockade may likely improve patients' long-term survival.
As for the short course (two cycles), we have the following considerations: firstly, the NICHE-2 trial, which adopted a two-cycle regimen, reported no recurrences during follow-up, suggesting that short-course anti-PD-1 therapy may be sufficient to improve the survival of patients with localized dMMR/MSI-H colorectal cancer. Secondly, the potential benefits of PD-1 blockade should be balanced against its toxicities, because patients with stage-II dMMR colorectal cancer generally have a good prognosis. Two cycles of PD-1 blockade have been shown to have a good safety profile, with low incidence of grade 3-4 and immune-related adverse events.
- Detailed Description
This is an open-label, multi-centre, randomised, phase III trial comparing the combination of PD-1 blockade + SOC versus SOC alone as adjuvant therapy for patients with high-risk stage-II dMMR/MSI-H colorectal cancer.
Primary Objective: To determine whether the addition of Tislelizumab can significantly improve disease-free survival (DFS) compared to standard of care in patients with high-risk stage-II colorectal cancer.
Secondary objectives:
* To determine whether the addition of Tislelizumab can significantly improve overall survival (OS) compared to standard of care
* To assess the adverse events (AE) profile (including immune-related adverse events, ir-AEs).
OUTLINE: Patients are randomized to 1 of 2 arms, stratified by cT4 status.
Arm 1 (experimental group): patients receive Tislelizumab 200mg intravenously on day 1, with or without adjuvant chemotherapy, and repeat the treatment on day 22. Patients undergo routine follow-up every 3 months for the first 3 years, and then every 6 months for the year 4-5.
Arm 2 (control group): patients receive standard of care (SOC), whether with surveillance alone, single-agent Capecitabine, or CapeOx/FOLFOX, at the discretion of the doctor in charge. Patients undergo routine follow-up every 3 months for the first 3 years, and then every 6 months for the year 4-5.
Statistics According to the statistical design, 180 patients (90 per arm) are to be randomized. The study is expected to take up to 36 months to complete accrual.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 180
- dMMR and/or MSI-H colorectal carcinoma that undergo surgical resection
- Pathologically confirmed as stage II (T3-4,N0), with at least one of the following risk factors:
- T4 (T4a and T4b)
- Vascular invasion (VI)
- Perineural invasion (PNI)
- Poor differentiation (including mucinous and signet-ring carcinoma)
- Obstruction and/or perforation before surgery
- Perioperative CT/MR/PET-CT find no signs of metastases
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 10 days prior to study start
- Aged 18-80
- No prior medical therapy (chemotherapy, immunotherapy, biologic or targeted therapy) or radiation therapy for the current cancer
- Adequate organ function
- Active autoimmune disease that has required systemic treatment in past 2 years
- Positive surgical margin (R1/R2 resection)
- Presence of post-operative complications that may preclude treatment
- Active infection requiring systemic therapy
- Any other malignant disease within the preceding 5 years with the exception of non-melanomatous skin cancer, carcinoma in situ and early stage disease with a recurrence risk <5%.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Tislelizumab Arm Tislelizumab Two cycles of Tislelizumab 200mg intravenously, on day 1 and day 22, with or without adjuvant chemotherapy Tislelizumab Arm Adjuvant chemotherapy Two cycles of Tislelizumab 200mg intravenously, on day 1 and day 22, with or without adjuvant chemotherapy Control Arm Adjuvant chemotherapy Receiving standard of Care (either with adjuvant chemotherapy or surveillance alone).
- Primary Outcome Measures
Name Time Method Disease-free survival (DFS) 3 years DFS (tumor-specific) is defined as time from randomization to tumor relapse or tumor-related death. DFS will be compared between treatment arms using the stratified log rank test at one-sided level 0.025. If zero DFS events are observed in a certain stratum at an interim analysis and unstratified log-rank is used, all subsequent analyses for DFS will use unstratified log-rank test.
- Secondary Outcome Measures
Name Time Method Overall survival (OS) 5 years OS is defined as time from randomization to death from any cause. Overall survival will be compared between treatment arms using the log-rank test.
Incidence of adverse events up to 30 days after last treatment Assessed by Common Terminology Criteria for Adverse Events version 4.0. The overall adverse event rates and the immune-related adverse event rates will be compared between treatment arms using Chi-square test or Fisher's exact test, as appropriate.
Trial Locations
- Locations (1)
Dept. of Colorectal Surgery, Sun Yat-sen University Cancer Center. Yuexiu District, Dongfeng East Road 651
🇨🇳Guangzhou, Guangdong, China