This is an open-label, multicenter, phase Ib/II combined trial of sitagliptin, XELOX chemotherapy regimen, and PD-1 monoclonal antibody in the treatment of proficient mismatch repair locally advanced colorectal cancer.
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).
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
138
Oxaliplatin 130mg/m2 for inducing chemotherapy in Day 1 every 3 weeks and repeat for two cycles.
Oral Capecitabine 1000 mg/m2 twice daily combined with oxaliplatin chemotherapy in Day 1 to Day 14 every 3 weeks and repeat for 2 cycles.
Anti-PD1 antibody 200mg/m2 in Day 1 after oxaliplatin Chemotherapy. Repeat every 3 weeks for 2 cycles.
Second Affiliated Hospital of Zhejiang University School of Medicine
Hangzhou, Zhejiang, China
RECRUITINGAdverse events (AEs)
for Ib study
Time frame: From date of first chemotherapy until the date of patients were discharged from hospital after receiving radical surgery, up to 20 weeks
Dose limiting toxicities (DLTs)
for Ib study
Time frame: The DLT observation period is from the day1 of the first cycle(C1D1) to the start of the day1 of the second cycle(C2D1) dosing, each cycle is 21 days.
Proportion of patients achieving tumor regression grade 0/1 (TRG 0/1)
for II study
Time frame: 1 day of postoperative pathological examination.
Surgical Complication
for II study
Time frame: within 30 days since operation
Proportion of patients achieving tumor regression grade 3 (TRG 3)
for II study
Time frame: 1 day of postoperative pathological examination.
Adverse events (AEs)
for II study
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
for Ib study
Time frame: 1 day of postoperative pathological examination.
Proportion of patients achieving pathological Complete Response
for Ib study
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Oral sitagliptin twice daily combined with oxaliplatin chemotherapy in Day 1 to Day 14 every 3 weeks and repeat for 2 cycles. In the phase Ib study, sitagliptin set at three dose groups: 100 mg/day, 200 mg/day, and 400 mg/day, and the primary endpoint of Ib study is to determine the DLT and recommended phase II dose (RP2D). The appropriate dose level of sitagliptin will be set based on the result of Ib study.
Time frame: 1 day of postoperative pathological examination.
Proportion of patients achieving Major Pathologic Response
for Ib study
Time frame: 1 day of postoperative pathological examination.
Area Under the Curve
for Ib study；quantitative measure of the total exposure of the body to a drug over a specific time period.
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
for Ib study; highest plasma or blood concentration of a drug achieved in the body after its administration.
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
for Ib study; the length of time required for a drug to reach its maximum (peak) plasma or blood concentration in the systemic circulation after administration.
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
for Ib study; the volume of plasma or blood completely cleared of a drug per unit time by the body's eliminating organs
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
for Ib study; the specific time required for the plasma or blood concentration of a drug in the systemic circulation to decrease by half from its peak level or steady-state level
Time frame: From date of first chemotherapy until the date of patients were discharged from hospital after receiving radical surgery, up to 20 weeks