Neoadjuvant Chemotherapy, Anti-PD-1 Antibody and Sitagliptin for Locally Advanced pMMR CRC (Neo-CD)

A Phase Ib/II Study of Neoadjuvant Chemotherapy Combined With Anti-PD-1 Antibody and DPP4 Inhibitor Sitagliptin for Locally Advanced pMMR Colorectal Cancer

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.

Study Overview

• Status: Recruiting
• Conditions: Colorectal Cancer
• Intervention / Treatment: Drug: Oxaliplatin; Drug: Capecitabine; Drug: Anti-PD-1 monoclonal antibody; Drug: Sitagliptin (DPP4 inhibitor)

Detailed Description

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
• Enrollment (Estimated): 138
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Jun Li, MD; Phone Number: +86 13777878061; Email: 2307016@zju.edu.cn
• Study Contact Backup: Name: Xinyi Zhou, MD; Phone Number: +86 18768115468; Email: 3100102575@zju.edu.cn

Study Locations

• China
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310000
      • Recruiting
      • Second Affiliated Hospital of Zhejiang University School of Medicine
      • Contact: Xinyi Zhou, MD; Phone Number: +86 18768115468; Email: 3100102575@zju.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Pathologically diagnosed colorectal adenocarcinoma
• Age ≥18 years old and ≤75 years old
• MRI/CT stage T3-4aNany and TanyN1-2, without distant metastasis
• Life expectancy of 1 year The above
• Informed consent, no contraindications to chemotherapy exist
• pMMR diagnosed by IHC

Exclusion Criteria:

• Refused to participate in this study
• Multifocal colorectal cancer
• Past history of malignant tumors, except for basal cell carcinoma/papillary thyroid carcinoma/various types of carcinoma in situ
• Unable to receive chemotherapy , such as but not limited to bone marrow suppression, etc
• Major organ diseases (such as but not limited to COPD, coronary heart disease and renal insufficiency, etc.) acute attack and or severe acute infectious diseases (such as but not limited to hepatitis, pneumonia and myocarditis, etc.),
• ASA score> 3
• Mental disorder or illiteracy or language and communication barriers cannot understand the research plan
• Colorectal tumor has obstruction or high risk of obstruction and or there is bleeding and/or perforation
• Peripheral sensory nerve disorder, unable to receive oxaliplatin chemotherapy
• Lateral pelvic lymph node metastasis (mainly supplied by internal iliac artery)
• Pregnancy or breastfeeding
• Unable to accept MRI examination
• Consecutive use of glucocorticoids for more than 3 days within 1 month before signing the consent form
• Diabetes or impaired glucose tolerance who may require drug intervention
• Other scenarios deemed inappropriate by the investigators

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: XELOX+sitagliptin+anti-PD-1; XELOX (oxaliplatin + capecitabine), sitagliptin and PD-1 monoclonal antibody	Drug: Oxaliplatin; Oxaliplatin 130mg/m2 for inducing chemotherapy in Day 1 every 3 weeks and repeat for two cycles.; Drug: Capecitabine; 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.; Drug: Anti-PD-1 monoclonal antibody; Anti-PD1 antibody 200mg/m2 in Day 1 after oxaliplatin Chemotherapy. Repeat every 3 weeks for 2 cycles.; Drug: Sitagliptin (DPP4 inhibitor); 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.
Active Comparator: XELOX; XELOX (oxaliplatin + capecitabine)	Drug: Oxaliplatin; Oxaliplatin 130mg/m2 for inducing chemotherapy in Day 1 every 3 weeks and repeat for two cycles.; Drug: Capecitabine; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse events (AEs)	for Ib study	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	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	1 day of postoperative pathological examination.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Surgical Complication	for II study	within 30 days since operation
Proportion of patients achieving tumor regression grade 3 (TRG 3)	for II study	1 day of postoperative pathological examination.
Adverse events (AEs)	for II study	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	1 day of postoperative pathological examination.
Proportion of patients achieving pathological Complete Response	for Ib study	1 day of postoperative pathological examination.
Proportion of patients achieving Major Pathologic Response	for Ib study	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.	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.	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.	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	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	From date of first chemotherapy until the date of patients were discharged from hospital after receiving radical surgery, up to 20 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
DPP4 activity in peripheral blood and tumor tissues	for Ib study;	From date of first chemotherapy until the date of patients were discharged from hospital after receiving radical surgery, up to 20 weeks
The changes in the immunoprofile of the tumor tissue sample among TRG0/1 and TRG2/3 patients	By using single-cell analysis, we comprehensively characterized the immune landscape in the tumor sample of CRC patients before and after neoadjuvant treatment.	3 months after surgery
2-year overall survival	for II study; The proportion of all study cases in which no death from any cause occurred within 2 years after surgery	2-year after surgery
2-year Disease-free survival	From date of first chemotherapy until the date of first documented recurrence of tumor or date of death from any cause，whichever came first，assessed up to 24 months.	From date of first chemotherapy until the date of first documented recurrence of tumor or date of death from any cause，whichever came first，assessed up to 24 months.

Collaborators and Investigators

• Sponsor: Second Affiliated Hospital, School of Medicine, Zhejiang University

Study record dates

Study Major Dates

• Study Start (Actual): April 9, 2026
• Primary Completion (Estimated): December 1, 2029
• Study Completion (Estimated): December 31, 2029

Study Registration Dates

• First Submitted: December 8, 2025
• First Submitted That Met QC Criteria: January 16, 2026
• First Posted (Actual): January 26, 2026

Study Record Updates

• Last Update Posted (Actual): May 13, 2026
• Last Update Submitted That Met QC Criteria: May 10, 2026
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Intestinal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colonic Diseases; Colorectal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Hypoglycemic Agents; Protease Inhibitors; Enzyme Inhibitors; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Azoles; Nucleic Acids, Nucleotides, and Nucleosides; Pharmacologic Actions; Chemical Actions and Uses; Coordination Complexes; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Nucleosides; Uracil; Pyrimidinones; Pyrazines; Deoxyribonucleosides; Fluorouracil; Triazoles; Capecitabine; Oxaliplatin; Sitagliptin Phosphate; Dipeptidyl-Peptidase IV Inhibitors; spartalizumab
• Other Study ID Numbers: SAHZU Jun LI

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No