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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:
Phase II Component
Study Procedures All participants will receive 2 cycles of the assigned neoadjuvant treatment, followed by radical surgery.
Primary Endpoints
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| XELOX+sitagliptin+anti-PD-1 | Experimental | XELOX (oxaliplatin + capecitabine), sitagliptin and PD-1 monoclonal antibody |
|
| XELOX | Active Comparator | XELOX (oxaliplatin + capecitabine) |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Oxaliplatin | Drug | Oxaliplatin 130mg/m2 for inducing chemotherapy in Day 1 every 3 weeks and repeat for two cycles. |
|
| 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. |
| 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 |
| 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 |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Jun Li, MD | Contact | +86 13777878061 | 2307016@zju.edu.cn | |
| Xinyi Zhou, MD | Contact | +86 18768115468 | 3100102575@zju.edu.cn |
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Second Affiliated Hospital of Zhejiang University School of Medicine | Recruiting | Hangzhou | Zhejiang | 310000 | China |
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Phase Ib Component The study adopts the 3+3 design, with sitagliptin set at three dose groups: 100 mg/day, 200 mg/day, and 400 mg/day.
Enrollment starts with 3 patients in Group 1. Dose escalates if no DLT; adds 3 patients if 1 DLT occurs. Escalation continues if ≤1/6 have DLT; stops and de-escalates if ≥2/6 have DLT. The study includes 9-18 patients, with no -1 dose group; the lower safe dose becomes MTD if needed.
Phase II Component The current study presets the TRG 0/1 rate at 20% for the XELOX chemotherapy group. The study expects a TRG 0/1 rate of 30% in the investigational group, representing a 10% relative increase in significant tumor regression compared to standard therapy.
This is a prospective, multicenter, two-stage randomized controlled interventional study based on a Bayesian adaptive design, with a maximum sample size of 120 patients.
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| Capecitabine | Drug | 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-PD-1 monoclonal antibody | Drug | Anti-PD1 antibody 200mg/m2 in Day 1 after oxaliplatin Chemotherapy. Repeat every 3 weeks for 2 cycles. |
|
| Sitagliptin (DPP4 inhibitor) | Drug | 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. |
|
| 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 |
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. |
| ID | Term |
|---|---|
| D015179 | Colorectal Neoplasms |
| ID | Term |
|---|---|
| D007414 | Intestinal Neoplasms |
| D005770 | Gastrointestinal Neoplasms |
| D004067 | Digestive System Neoplasms |
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
| D004066 | Digestive System Diseases |
| D005767 | Gastrointestinal Diseases |
| D003108 | Colonic Diseases |
| D007410 | Intestinal Diseases |
| D012002 | Rectal Diseases |
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| ID | Term |
|---|---|
| D000077150 | Oxaliplatin |
| D000069287 | Capecitabine |
| C000711728 | spartalizumab |
| D000068900 | Sitagliptin Phosphate |
| D054873 | Dipeptidyl-Peptidase IV Inhibitors |
| ID | Term |
|---|---|
| D056831 | Coordination Complexes |
| D009930 | Organic Chemicals |
| D003841 | Deoxycytidine |
| D003562 | Cytidine |
| D011741 | Pyrimidine Nucleosides |
| D011743 | Pyrimidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D005472 | Fluorouracil |
| D014498 | Uracil |
| D011744 | Pyrimidinones |
| D003853 | Deoxyribonucleosides |
| D009705 | Nucleosides |
| D009706 | Nucleic Acids, Nucleotides, and Nucleosides |
| D014230 | Triazoles |
| D001393 | Azoles |
| D011719 | Pyrazines |
| D011480 | Protease Inhibitors |
| D004791 | Enzyme Inhibitors |
| D045504 | Molecular Mechanisms of Pharmacological Action |
| D020228 | Pharmacologic Actions |
| D020164 | Chemical Actions and Uses |
| D007004 | Hypoglycemic Agents |
| D045505 | Physiological Effects of Drugs |
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