Neoadjuvant Chemotherapy, Anti-PD-1 Antibody and Sitagliptin for Locally Advanced pMMR CRC

Most colorectal cancer (CRC) cases are classified as proficient mismatch repair (pMMR) CRC. This subtype is insensitive to single-agent immunotherapy, with chemotherapy remaining the primary pharmacotherapeutic intervention. Approximately 30% of colon cancer patients develop recurrence and metastasis following initial radical resection combined with 6 months of adjuvant chemotherapy.

Neoadjuvant chemotherapy (NACT) for tumor downstaging and survival improvement represents a standard approach for locally advanced tumors. However, its application is limited to select rectal cancer populations, and its role in colon cancer remains controversial-primarily due to inadequate tumor regression observed with current regimens. Given that deep tumor regression correlates with improved survival, there is a critical need to enhance NACT efficacy.

Neo-CD adopts a combined phase Ib/II study design. Phase Ib Component

* Design: Single-center trial utilizing the traditional 3+3 dose-escalation principle. * Objectives:

1. Evaluate the safety of sitagliptin in combination with XELOX (oxaliplatin + capecitabine) and anti-PD-1 monoclonal antibody as neoadjuvant therapy for CRC. 2. Determine the recommended phase II dose (RP2D) of sitagliptin. 3. Explore the combination's potential for significant tumor regression and modulation of the tumor immune microenvironment.

Phase II Component

* Design: Prospective, multicenter, randomized controlled superiority trial. * Objective: Compare the efficacy of neoadjuvant XELOX + sitagliptin + anti-PD-1 versus standard neoadjuvant XELOX in locally advanced CRC, with a focus on significant tumor regression (TRG 0/1 rate).

Study Procedures All participants will receive 2 cycles of the assigned neoadjuvant treatment, followed by radical surgery.

Primary Endpoints

* Phase Ib: Incidence of adverse events (AEs), serious adverse events (SAEs), and dose-limiting toxicity (DLT). * Phase II: Proportion of patients achieving tumor regression grade 0/1 (TRG 0/1).

• Surgical Complication [Time frame: within 30 days since operation]
• Proportion of patients achieving tumor regression grade 3 (TRG 3) [Time frame: 1 day of postoperative pathological examination.]
• Adverse events (AEs) [Time frame: From date of first chemotherapy until the date of patients were discharged from hospital after receiving radical surgery, up to 20 weeks]
• Proportion of patients achieving tumor regression grade 0/1 [Time frame: 1 day of postoperative pathological examination.]
• Proportion of patients achieving pathological Complete Response [Time frame: 1 day of postoperative pathological examination.]
• Proportion of patients achieving Major Pathologic Response [Time frame: 1 day of postoperative pathological examination.]
• Area Under the Curve [Time frame: From date of first chemotherapy until the date of patients were discharged from hospital after receiving radical surgery, up to 20 weeks]
• Maximum Concentration [Time frame: From date of first chemotherapy until the date of patients were discharged from hospital after receiving radical surgery, up to 20 weeks]
• Time to Maximum Concentration [Time frame: From date of first chemotherapy until the date of patients were discharged from hospital after receiving radical surgery, up to 20 weeks]
• Clearance [Time frame: From date of first chemotherapy until the date of patients were discharged from hospital after receiving radical surgery, up to 20 weeks]
• Half-Life [Time frame: From date of first chemotherapy until the date of patients were discharged from hospital after receiving radical surgery, up to 20 weeks]