Adjuvant PD-1 Blockade for High-risk Stage-II DMMR/MSI-H Colorectal Cancer (SMALLER)

Sun Yat-sen University

Status and phase: Enrolling; Phase 3

Conditions: Microsatellite Instability High; Colorectal Cancer

Treatments: Drug: Tislelizumab; Drug: Adjuvant chemotherapy

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT06520683

2024-FXY-219

Details and patient eligibility

About

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.

Full 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.

Enrollment: 180 estimated patients

Sex: All

Ages: 18 to 80 years old

Volunteers: No Healthy Volunteers

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%.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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180 participants in 2 patient groups

Tislelizumab Arm

Experimental group

Description:

Two cycles of Tislelizumab 200mg intravenously, on day 1 and day 22, with or without adjuvant chemotherapy

Treatment:

Drug: Adjuvant chemotherapy

Drug: Tislelizumab

Control Arm

Active Comparator group

Description:

Receiving standard of Care (either with adjuvant chemotherapy or surveillance alone).

Treatment:

Drug: Adjuvant chemotherapy