YMN-A02 for Advanced pMMR Colorectal Cancer With Liver Metastases

A Phase I Clinical Trial of YMN-A02 in Patients With Advanced pMMR Colorectal Cancer and Liver Metastases: Safety, Tolerability, and Preliminary Efficacy

This study was a prospective, single-center, open-label, single-arm, multi-dose ascending phase Ⅰ clinical trial. The investigators constructed a TM10-LNP mRNA preparation encoding CTLA-4 antibody and TGF-β trap bifunction protein (YMN-A02 bifunction RNA preparation). The aim of this study is to provide a new strategy for overcoming the immune tolerance of liver tumors and improving the response rate of immunotherapy. The investigators planned to enroll patients with advanced pMMR liver metastasis from colorectal cancer who failed standard treatment. A modified "3+3" design was used, and 10 patients were expected to be enrolled. There were four dose groups of 100μg, 250μg, 500μg and 1000μg. The trial used a modified "3+3" dose climbing design, in which one subject was set as a sentinel patient in the initial 100μg dose group. If the subject did not experience DLT during the DLT observation period, the dose was judged safe and escalation to the next group occurred. If DLT occurred, 3 additional subjects in this group would be required for further evaluation. In the subsequent 250μg, 500μg, and 1000μg dose groups, three subjects were enrolled first in each group: if there was no DLT, the number of subjects was increased. If ≥2 of the 3 cases had DLT, the escalation was terminated. If DLT occurred in 1 out of 3 subjects, 3 additional observations would be made in the same dose group. If the incidence of DLT in the total 6 subjects did not exceed 1/6 after the supplement, the escalation could be escalated. Otherwise, the escalation was terminated and the dose was considered as intolerable.

Study Overview

• Status: Not yet recruiting
• Conditions: Colorectal Cancer With Liver Metastatic
• Intervention / Treatment: Biological: YMN-A02 100μg; Biological: YMN-A02 250μg; Biological: YMN-A02 500μg; Biological: YMN-A02 1000μg

• Study Type: Interventional
• Enrollment (Estimated): 10
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Peng Xingchen Peng; Phone Number: 86-17723609529; Email: pxx2014@163.com

Study Locations

• China
  • Sichuan
    • Chengdu, Sichuan, China, 610041
      • West China Hospital
      • Contact: Peng Xingchen Professor; Phone Number: 86-18980606753; Email: pxx2014@scu.edu.cn

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Signed the informed consent form approved by the ethics committee.
2. 18-70 years old; ECOG performance status 0-1.
3. Histologically or cytologically confirmed colorectal cancer with liver metastases, molecularly classified as pMMR (presence of other distant metastases allowed).

4. Patients who have failed or are intolerant to standard therapy, or who refuse standard therapy.

   1. For patients with RAS/BRAF wild-type and eligible for targeted therapy: enrollment allowed only after disease progression on a prior standard regimen containing anti-EGFR or anti-VEGF monoclonal antibody.
   2. For patients with BRAF V600E mutation: enrollment allowed only after failure of a prior BRAF inhibitor-containing chemotherapy regimen.
   3. For patients who do not meet the above molecular characteristics: enrollment allowed only after failure of at least two prior lines of systemic chemotherapy (including a platinum-containing regimen).
5. At least one measurable liver metastasis (CT scan long diameter ≥10 mm, slice thickness ≤5 mm).
6. Life Expectancy≥3 months.

7. Adequate Major Organ Function (all within 14 days before randomization):

   1. Hemoglobin ≥80 g/L (no transfusion within 14 days); absolute neutrophil count >1.5×10⁹/L; platelet count ≥80×10⁹/L.
   2. Total bilirubin ≤1.5×ULN; ALT/AST ≤2.5×ULN (or ≤5×ULN in the presence of liver metastases); creatinine clearance ≥60 mL/min (Cockcroft-Gault formula).
   3. Left ventricular ejection fraction (LVEF) ≥50%.
8. Good compliance, and family agrees to cooperate with survival follow-up.

Exclusion Criteria:

1. Participation in another interventional drug trial within 4 weeks before enrollment.
2. Prior or concurrent other malignancy, except: carcinoma in situ of the cervix, cutaneous squamous cell carcinoma, superficial bladder tumor, or any other malignancy that has been curatively treated and recurrence-free for ≥5 years.
3. Poorly controlled heart disease or clinical symptoms, including but not limited to: NYHA class ≥2 heart failure, unstable angina, myocardial infarction within 1 year, or clinically significant supraventricular or ventricular arrhythmia requiring treatment or intervention.
4. Pregnant or breastfeeding women.
5. Active infection, including but not limited to: active tuberculosis, systemic bacterial or fungal infection (NCI-CTCAE v5.0 grade ≥2), HIV infection, active HBV (HBV DNA >ULN), or active HCV (HCV RNA >ULN).
6. History of substance abuse that cannot be abstained from, or history of psychiatric disorders.
7. Active or history of autoimmune disease (including but not limited to uveitis, enteritis, hypophysitis, nephritis, hyperthyroidism, hypothyroidism, etc.). Exceptions: vitiligo controlled with only topical agents; childhood asthma completely resolved without any intervention in adulthood. Patients with asthma requiring bronchodilators for medical intervention are excluded.
8. Prior vaccination with any mRNA-based drug or mRNA formulation.
9. Prior participation in any clinical trial involving lipid nanoparticle (LNP) formulations.
10. Contraindications to intravenous infusion.
11. History of drug abuse, or any medical, psychological, or social condition (e.g., alcoholism or drug addiction) that, in the investigator's judgment, may affect study compliance.
12. Known allergy, hypersensitivity, or intolerance to any component (active substance or excipients) of the study drug; history of severe allergy to drugs, food, or vaccines, including but not limited to anaphylactic shock, angioedema of the larynx, anaphylactic dyspnea, allergic purpura, thrombocytopenic purpura, or Arthus reaction.
13. Plan to conceive (either female subject or partner of male subject) from screening through 12 months after the last dose.
14. Any concurrent condition that, in the investigator's judgment, may compromise patient safety or interfere with study completion.

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

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: YMN-A02 100 μg Group; Enrolled subjects will receive a 100 μg intravenous infusion.	Biological: YMN-A02 100μg; Enrolled subjects will receive a 100 μg intravenous infusion according to their assigned dose group. The dosing regimen includes 5 doses of primary immunization followed by subsequent individualized treatment. The first 4 doses of primary immunization are administered once weekly (Q1W), and the 5th dose is administered one month after the 4th dose. The DLT observation period is from the first infusion to 14 days after the third infusion.; Other Names: YMN-A02
Experimental: YMN-A02 250 μg Group; Enrolled subjects will receive a 250 μg intravenous infusion.	Biological: YMN-A02 250μg; Enrolled subjects will receive a 250 μg intravenous infusion according to their assigned dose group. The dosing regimen includes 5 doses of primary immunization followed by subsequent individualized treatment. The first 4 doses of primary immunization are administered once weekly (Q1W), and the 5th dose is administered one month after the 4th dose. The DLT observation period is from the first infusion to 14 days after the third infusion.
Experimental: YMN-A02 500 μg Group; Enrolled subjects will receive a 500 μg intravenous infusion.	Biological: YMN-A02 500μg; Enrolled subjects will receive a 500 μg intravenous infusion according to their assigned dose group. The dosing regimen includes 5 doses of primary immunization followed by subsequent individualized treatment. The first 4 doses of primary immunization are administered once weekly (Q1W), and the 5th dose is administered one month after the 4th dose. The DLT observation period is from the first infusion to 14 days after the third infusion.
Experimental: YMN-A02 1000 μg Group; Enrolled subjects will receive a 1000 μg intravenous infusion.	Biological: YMN-A02 1000μg; Enrolled subjects will receive a 1000 μg intravenous infusion according to their assigned dose group. The dosing regimen includes 5 doses of primary immunization followed by subsequent individualized treatment. The first 4 doses of primary immunization are administered once weekly (Q1W), and the 5th dose is administered one month after the 4th dose. The DLT observation period is from the first infusion to 14 days after the third infusion.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Occurrence of Dose-Limiting Toxicity (DLT)	Observe and record the occurrence of DLTs. DLT is defined as treatment-related adverse events or clinically significant laboratory abnormalities occurring during the DLT observation period, graded according to NCI CTCAE v5.0.	From first dose to 14 days after the third dose, approximately Day 0 to Day 42

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-Free Survival (PFS)	Assess disease progression per RECIST v1.1, calculating the time from start of treatment to first documented disease progression or death from any cause.	Within 2 years after the first dose
Objective Response Rate (ORR)	Tumor response assessed per RECIST v1.1 for solid tumors. ORR is the proportion of patients whose tumor volume reduction reaches a predefined value and is maintained for a minimum required duration, calculated as the sum of complete response (CR) and partial response (PR) rates.	Within 6 months after the first dose

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in Peripheral Blood Lymphocyte Subsets	Peripheral blood lymphocytes will be isolated from whole blood using lymphocyte separation medium. Flow cytometry will be used to detect T cells, B cells, macrophages, NK cells, and regulatory T cells (Tregs).	Baseline (Day 1 pre-infusion); Day 8 (before the 2nd infusion); Day 22 (before the 4th infusion); Days 29-36 (7-14 days after the 4th infusion); Days 41-55 (19-33 days after the 4th infusion)
Percentage of Dendritic Cells Expressing Maturation/Activation Markers	Dendritic cells (DCs) will be isolated from peripheral blood and labeled with antibodies against surface markers CD80, CD86, and MHC class II molecules. Flow cytometry will be performed to determine the percentage of DCs positive for each marker. Maturation and activation status are assessed based on these percentages	Baseline (Day 1 pre-infusion); Day 8 (before the 2nd infusion); Day 22 (before the 4th infusion); Days 29-36 (7-14 days after the 4th infusion); Days 41-55 (19-33 days after the 4th infusion)
Tumor-Infiltrating CD8+ T Cells	Tumor tissue sections will be stained to identify CD8+ T cells, including stem-like and exhausted CD8+ T cell subsets. Confocal microscopy and flow cytometry (using single-cell suspensions from tumor tissue) will be used to observe the infiltration status of these cells.	Baseline (Day 1 pre-infusion); Day 8 (before the 2nd infusion); Day 22 (before the 4th infusion); Days 29-36 (7-14 days after the 4th infusion); Days 41-55 (19-33 days after the 4th infusion)
Cytokine Levels Associated with Delayed-Type Hypersensitivity (DTH)	Plasma will be collected 24-72 hours after administration. ELISA kits will be used to measure the levels of cytokines including IL-12, IFN-γ, IL-2, and IL-10 to assess the cellular immune response and the impact of the product on immune function.	Baseline (Day 1 pre-infusion); Day 8 (before the 2nd infusion); Day 22 (before the 4th infusion); Days 29-36 (7-14 days after the 4th infusion); Days 41-55 (19-33 days after the 4th infusion)

Collaborators and Investigators

• Sponsor: West China Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): July 30, 2026
• Primary Completion (Estimated): June 30, 2028
• Study Completion (Estimated): June 30, 2028

Study Registration Dates

• First Submitted: April 26, 2026
• First Submitted That Met QC Criteria: May 20, 2026
• First Posted (Actual): May 28, 2026

Study Record Updates

• Last Update Posted (Actual): May 28, 2026
• Last Update Submitted That Met QC Criteria: May 20, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Other Study ID Numbers: 2026(890)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No