Colorectal Cancer, Microsatellite Instability High
Conditions
Keywords
Adjuvant therapy, Stage II CRC, dMMR/MSI-H, PD-1 blockade
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.
Interventions
DRUGTislelizumab
\- Tislelizumab 200mg (day 1 and day 22), administered after surgery
DRUGAdjuvant chemotherapy
* Adjuvant therapy is not mandatory. * Optional adjuvant regimens include FOLFOX, CapeOX, 5-FU+LV, or Capecitabine.
Sponsors
BeiGene
Sun Yat-sen University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* 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: 1) T4 (including T4a and T4b); 2) Vascular invasion; 3) Perineural invasion; 4) Poor differentiation (including mucinous and signet-ring carcinoma); 5) 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
Exclusion criteria
* 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%.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
China
Contacts
Primary ContactBin-Yi Xiao, M.D.
Outcome results
None listed