YMN-A02 for Advanced Primary Hepatocellular Carcinoma.

A Phase I Clinical Study of YMN-A02, a Bifunctional RNA Agent, for Safety, Tolerability, and Preliminary Efficacy in Patients With Advanced Primary Liver Cancer Who Have Failed Standard of Care

Primary liver cancer (Hepatocellular carcinoma, HCC) represents a major challenge in clinical oncology and poses a serious threat to public health. In recent years, the application of immune checkpoint inhibitors (ICIs) has transformed the landscape of cancer therapy, demonstrating remarkable efficacy in a subset of patients. However, due to the unique immune-tolerant microenvironment of the liver, tumor cells can evade host immune surveillance, leading to reduced immune cell infiltration and T cell exhaustion. Consequently, patients with advanced HCC often respond poorly to existing ICI therapies. Transforming growth factor-beta (TGF-β), a key regulator of T cell immune responses, is highly expressed in the tumor microenvironment and mediates immune evasion by inducing regulatory T cell (Treg) differentiation and suppressing the effector functions of CD8⁺ T cells. Therefore, simultaneous blockade of immune checkpoints and the TGF-β signaling pathway represents a promising strategy to reverse immune tolerance in liver tumors.

Based on the above mechanisms, our research team has developed an RNA formulation (YMN-A02 bifunctional RNA formulation) encapsulated in TM10-LNP, which encodes a bifunctional fusion protein combining a CTLA-4 antibody and a TGF-β trap. Preclinical studies have shown that this formulation effectively activates antitumor immune responses and inhibits tumor growth in orthotopic liver cancer animal models. This study proposes a Phase I clinical trial to evaluate the safety, tolerability, immunogenicity, and preliminary efficacy of this formulation in patients with advanced primary liver cancer who have failed standard treatment, aiming to provide a new strategy for overcoming immune tolerance in liver tumors and improving the response rate to immunotherapy.

Study Overview

• Status: Not yet recruiting
• Conditions: Hepatocellular Carcinoma
• 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: 86-017723609529; Email: pxx2014@163.com

Study Locations

• China
  • Sichuan
    • Chengdu, Sichuan, China, 610041
      • West China Hospital
      • Contact: Peng Xingchen Professor; Phone Number: 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. Informed consent: Signed informed consent form approved by the ethics committee.
2. Age and performance status: Aged 18-70 years; Eastern Cooperative Oncology Group (ECOG) performance status score of 0-1.
3. Patients with histologically confirmed advanced primary hepatocellular carcinoma that has progressed after treatment with anti-angiogenic targeted therapy and immune checkpoint inhibitors.
4. At least one target lesion with a measurable diameter according to RECIST criteria (longest diameter of tumor lesion ≥10 mm on CT scan; short diameter of lymph node lesion ≥10 mm on CT scan; slice thickness ≤5 mm).
5. Life expectancy: ≥3 months.

6. Adequate major organ function, as verified by the following laboratory and test results obtained within 14 days prior to randomization:

   Hematology: Hemoglobin ≥80 g/L (no blood transfusion within 14 days); absolute neutrophil count >1.5×10⁹/L; platelet count ≥80×10⁹/L.

   Biochemistry: Total bilirubin ≤1.5× upper limit of normal (ULN); alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤2.5×ULN; if liver metastases are present, ALT or AST ≤5×ULN; endogenous creatinine clearance ≥60 mL/min (Cockcroft-Gault formula).

   Cardiac assessment: Left ventricular ejection fraction (LVEF) ≥50% as assessed by Doppler echocardiography.

7. Good compliance and follow-up agreement: The patient is compliant and the family agrees to cooperate with survival follow-up.

Exclusion Criteria:

1. Participation in another clinical trial of an investigational drug within 4 weeks prior to enrollment.
2. Previous or concurrent diagnosis of another malignancy, except for the following: carcinoma in situ of the cervix, cutaneous squamous cell carcinoma, urothelial carcinoma of the bladder that has been treated with curative intent, or any other malignancy that has been treated with curative intent with no evidence of recurrence for 5 years or more.
3. Presence of poorly controlled cardiac disease or clinical symptoms, including but not limited to: New York Heart Association (NYHA) Class ≥2 heart failure, unstable angina, myocardial infarction within the past year, or clinically significant supraventricular or ventricular arrhythmia requiring treatment or intervention.
4. Pregnant or breastfeeding women.
5. Presence of active infection, including but not limited to: active tuberculosis, bacterial or fungal infection requiring systemic treatment (NCI-CTCAE v5.0 Grade ≥2), human immunodeficiency virus (HIV) infection, active hepatitis B virus (HBV) infection (HBV DNA above the upper limit of normal), or active hepatitis C virus (HCV) infection (HCV RNA above the upper limit of normal).
6. History of psychotropic substance abuse that cannot be abstained from, or history of mental disorders.
7. Presence of active autoimmune disease or history of autoimmune disease (including but not limited to: uveitis, enteritis, hypophysitis, nephritis, hyperthyroidism, hypothyroidism, etc.). The following are exceptions: vitiligo controlled with topical medication only; childhood asthma that has completely resolved and requires no intervention in adulthood; patients with asthma requiring bronchodilators for medical intervention are not eligible.
8. Prior vaccination with any mRNA-based drug or mRNA formulation.
9. Prior participation in clinical trials involving lipid nanoparticle (LNP) formulations.
10. Contraindications to intravenous infusion.
11. History of drug abuse, or medical, psychological, or social conditions (such as history of alcoholism or drug addiction) that, in the investigator's judgment, may affect compliance with the study.
12. Known allergy, hypersensitivity, or intolerance to any component of the study formulation (including active ingredients and excipients); history of severe drug, food, or vaccine allergy, including but not limited to: anaphylactic shock, allergic laryngeal edema, allergic dyspnea, anaphylactoid purpura, thrombocytopenic purpura, or Arthus reaction.
13. Pregnancy plan (for female subjects or partners of male subjects) from the screening period until 12 months after the last dose.
14. Any concomitant disease that, in the investigator's judgment, may jeopardize patient safety or interfere with the completion of the study.

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.
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).	Samples will be collected at baseline, before the 2nd and 4th infusions, and after infusion (7-14 days and 19-33 days) to evaluate the effect of the investigational product.
Maturation and Activation of Dendritic Cells (DCs)	DCs will be isolated from peripheral blood and labeled with antibodies against surface markers CD80, CD86, and MHC molecules. Flow cytometry will be performed to assess the maturation, activation status, and antigen-presenting function of DCs.	Assessment time points include baseline, pre-infusion (2nd and 4th), and post-infusion (7-14 days and 19-33 days).
Antigen-specific T Cell Activation Assessed by ELISPOT	Peripheral blood lymphocytes will be seeded onto IFN-γ coated ELISPOT plates and cultured at 37°C with 5% CO2 for 48 hours. Spot-forming cells (SFCs) will be counted using an ELISPOT reader to evaluate T cell activation induced by the product.	Assessment time points include baseline, pre-infusion (2nd and 4th), and post-infusion (7-14 days and 19-33 days).
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, prior to the 2nd and 4th infusions, and post-infusion (days 7-14 and days 19-33).

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 5, 2026
• First Posted (Actual): May 12, 2026

Study Record Updates

• Last Update Posted (Actual): May 12, 2026
• Last Update Submitted That Met QC Criteria: May 5, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Digestive System Neoplasms; Digestive System Diseases; Liver Diseases; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Liver Neoplasms; Carcinoma; Carcinoma, Hepatocellular
• Other Study ID Numbers: 2026(889)

Drug and device information, study documents

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