Personalized Tumor Neoantigen mRNA Therapy for Advanced Hepatocellular Carcinoma

Phase 1

Recruiting

• Conditions: Advanced Hepatocellular Carcinoma (HCC)
• Interventions: Procedure: TACE; Drug: Sintilimab combined with Bevacizumab; Biological: individualized anti-tumor new antigen iNeo-Vac-R01 injection

• Registration Number: NCT06995105
• Lead Sponsor: Zhejiang University

Brief Summary

This study is to evaluate the feasibility and safety of personalized tumor neoantigen mRNA therapy iNeo-Vac-R01 combined with PD-1 monoclonal antibody, anti-VEGFR monoclonal antibody and TACE regimen for the treatment of patients with advanced hepatocellular carcinoma.

Detailed Description

Not available

Study Timeline

• Study Start: 2025-04-09
• Study First Submitted: 2025-04-09
• Status Verified: 2025-05
• Study First Submitted QC: 2025-05-20
• Last Update Submitted: 2025-05-20
• Study First Posted: 2025-05-29
• Last Update Posted: 2025-05-29
• Primary Completion: 2027-04-01
• Study Completion: 2028-04-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 30

Inclusion Criteria

• (1) Subjects who meet all the following inclusion criteria will enter the pre-screening stage of this study and undergo the lesion puncture process:

  1. Voluntarily sign the informed consent form;

  2. Aged ≥18 years and ≤75 years, regardless of gender;

  3. Strictly meet the 2018 American Association for Clinical Diagnosis of Liver Diseases (AASLD) clinical diagnostic criteria for HCC, and imaging assessment is unresectable/metastatic hepatocellular carcinoma (HCC), CNLC stage Ib to IIIb;

  4. Have not received systemic or local treatment for HCC in the past.

  5. According to the solid tumor efficacy evaluation criteria (RECIST 1.1), the investigators assess the presence of measurable lesions.

  6. Child-Pugh score within 7 points (including 7 points)

  7. Eastern Cooperative Oncology Group (ECOG) performance status score is 0 or 1;

  8. Adequate fresh tumor tissue samples can be obtained for exome and transcriptome sequencing analysis;

  9. The main organ functions of the heart, liver and kidney are normal:

     1. QTc (corrected QT interval) in the electrocardiogram: ≤450 milliseconds for men, or ≤470 milliseconds for women;
     2. Coagulation function: international normalized ratio (INR) ≤1.5×ULN; activated partial thromboplastin time (APTT) ≤1.5 times ULN;
     3. Hematological indicators: white blood cells ≥3.5×109/L; absolute neutrophil count (ANC) ≥1.5×109/L; hemoglobin (HGB) ≥10 g/dL; platelet count (PLT) ≥80×109/L;
     4. Biochemical indicators: serum total bilirubin (TBIL) ≤ 1.5 times the upper limit of normal (ULN); alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 times ULN (ALT or AST ≤ 5 times ULN is allowed for patients with liver metastasis and liver cancer); serum creatinine and urea nitrogen ≤ 1.5 times ULN;

  10. Male patients with fertility and female patients of childbearing age agree to take effective contraceptive measures from the signing of the informed consent form to 6 months after the last administration of the trial drug; women of childbearing age include premenopausal women and women within 2 years after menopause;

  11. Able to follow the study protocol and follow-up process.

  (2) Subjects who meet all the following inclusion criteria will enter the formal screening phase of this study and enter the study medication process:

  1. Voluntarily sign the informed consent form;

  2. Aged ≥18 years and ≤75 years, regardless of gender;

  3. Primary hepatocellular carcinoma confirmed by pathology (histology or cytology);

  4. Have not received any systemic treatment.

  5. According to the solid tumor efficacy evaluation criteria (RECIST 1.1), the researcher assesses the presence of measurable lesions.

  6. Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1;

  7. Normal function of the heart, liver and kidney:

     1. QTc (corrected QT interval) in the electrocardiogram: ≤450 milliseconds for men, or ≤470 milliseconds for women;
     2. Coagulation function: international normalized ratio (INR) ≤1.5×ULN; activated partial thromboplastin time (APTT) ≤1.5 times ULN;
     3. Hematological indicators: white blood cells ≥3.5×109/L; absolute neutrophil count (ANC) ≥1.5×109/L; hemoglobin (HGB) ≥10 g/dL; platelet count (PLT) ≥80×109/L;
     4. Biochemical indicators: serum total bilirubin (TBIL) ≤ 1.5 times the upper limit of normal (ULN); alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 times ULN (ALT or AST ≤ 5 times ULN is allowed for patients with liver metastasis and liver cancer); serum creatinine and urea nitrogen ≤ 1.5 times ULN;

  8. Male patients with fertility and female patients of childbearing age agree to take effective contraceptive measures from the signing of the informed consent form to 6 months after the last administration of the trial drug; women of childbearing age include premenopausal women and women within 2 years after menopause;

  9. Able to follow the study protocol and follow-up process.

Exclusion Criteria

• 1. Diffuse HCC. 2) Known fibrolamellar HCC, cholangiocarcinoma, and mixed HCC. 3) Concomitant tumor thrombus in the main portal vein or contralateral portal vein, superior mesenteric vein, or vena cava.

  2. History of meningeal disease; presence of central nervous system metastases or meningeal metastases.

  3. History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonia, or idiopathic pneumonia, or evidence of active pneumonia on screening chest CT.

  4. Patients with other malignant tumors at the same time, but basal cell carcinoma, thyroid cancer, cervical atypical hyperplasia, etc. that have been cured, have been in a disease-free state for more than 5 years or are considered by researchers to be less likely to relapse; 7) Patients with a history of bone marrow transplantation, allogeneic organ transplantation, or allogeneic hematopoietic stem cell transplantation; 8) Patients with immunosuppressants, that is, those who need to take immunosuppressants regularly 4 weeks before the screening period and during the clinical study, including but not limited to the following: those with severe asthma, autoimmune diseases or immunodeficiency, those who are treated with immunosuppressive drugs, and those with a known history of primary immunodeficiency; but excluding type 1 diabetes, autoimmune-related hypothyroidism requiring hormone treatment, and vitiligo and psoriasis that do not require systemic treatment; 9) Active bacterial or fungal infection confirmed by clinical diagnosis; active tuberculosis or history of tuberculosis; 10) Those with positive human immunodeficiency virus (HIV) antibody test, positive Treponema pallidum (TP) antibody test, active hepatitis C (positive hepatitis C virus (HCV) antibody and HCV RNA result is positive), active hepatitis B; 11) Herpes virus infection (except for those with scabs for more than 4 weeks); respiratory virus infection (except for those who have recovered for more than 4 weeks); 12) Uncontrolled complications include but are not limited to active infection, symptomatic congestive heart failure, unstable angina, arrhythmia; severe coronary artery disease or cerebrovascular disease, or other diseases that the investigators believe are not suitable for inclusion; 13) History of drug abuse, clinical, psychological or social factors that affect informed consent or research implementation; history of mental illness; 14) History of food, drug or vaccine allergy, or other potential immunotherapy allergies considered by the investigator.

  5. Pregnant or lactating women; 16) Those who the investigators believe are not suitable for inclusion or may not be able to complete this trial for other reasons.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Experimental group (mRNA therapy+PD-1+anti-VEGFR+TACE)	TACE	1. After pathological diagnosis, the patient will pass the screening of the inclusion group and enter the study medication process; 2. During the screening period, the patient can start TACE treatment first, and the subsequent treatment will be arranged by the researcher based on the patient's physical condition, disease progression, etc. The total number shall ≤ 4 times, and the interval between each two times shall be at least 4 weeks; 3. After the patient enters the study medication process, he/she needs to first use sintilimab (200 mg) combined with bevacizumab (Dayoutong injection, 15 mg/kg), intravenous infusion, once every 3 weeks, until the patient is intolerant or the tumor progresses; the first use of sintilimab and Dayutong injection is the first day (D1) 4. D43±3 (week 7±3 days), the first efficacy evaluation, if the patient has no disease progression, he/she will receive treatment (sintilimab Q3W + bevacizumab Q3W + the first batch of personalized mRNA inject Q3W)
Experimental group (mRNA therapy+PD-1+anti-VEGFR+TACE)	Sintilimab combined with Bevacizumab	1. After pathological diagnosis, the patient will pass the screening of the inclusion group and enter the study medication process; 2. During the screening period, the patient can start TACE treatment first, and the subsequent treatment will be arranged by the researcher based on the patient's physical condition, disease progression, etc. The total number shall ≤ 4 times, and the interval between each two times shall be at least 4 weeks; 3. After the patient enters the study medication process, he/she needs to first use sintilimab (200 mg) combined with bevacizumab (Dayoutong injection, 15 mg/kg), intravenous infusion, once every 3 weeks, until the patient is intolerant or the tumor progresses; the first use of sintilimab and Dayutong injection is the first day (D1) 4. D43±3 (week 7±3 days), the first efficacy evaluation, if the patient has no disease progression, he/she will receive treatment (sintilimab Q3W + bevacizumab Q3W + the first batch of personalized mRNA inject Q3W)
Experimental group (mRNA therapy+PD-1+anti-VEGFR+TACE)	individualized anti-tumor new antigen iNeo-Vac-R01 injection	1. After pathological diagnosis, the patient will pass the screening of the inclusion group and enter the study medication process; 2. During the screening period, the patient can start TACE treatment first, and the subsequent treatment will be arranged by the researcher based on the patient's physical condition, disease progression, etc. The total number shall ≤ 4 times, and the interval between each two times shall be at least 4 weeks; 3. After the patient enters the study medication process, he/she needs to first use sintilimab (200 mg) combined with bevacizumab (Dayoutong injection, 15 mg/kg), intravenous infusion, once every 3 weeks, until the patient is intolerant or the tumor progresses; the first use of sintilimab and Dayutong injection is the first day (D1) 4. D43±3 (week 7±3 days), the first efficacy evaluation, if the patient has no disease progression, he/she will receive treatment (sintilimab Q3W + bevacizumab Q3W + the first batch of personalized mRNA inject Q3W)

Primary Outcome Measures

Name	Time	Method
Adverse events	The evaluation period was the dosing observation period and the safety follow-up period (21±3 days after the last dose).	According to the Commonly Used Adverse Event Criteria (CTCAE version 5.0), the number of subjects with adverse events and/or dose-limiting toxicity was counted as an indicator of the safety and tolerable dose of iNeo-Vac-R01 injection.

Secondary Outcome Measures

Name	Time	Method
Conversion rate	Up to 2 years	the proportion of patients with initially inoperable tumors who are successfully converted to patients who can undergo radical surgical resection after systemic treatment in conversion therapy
Overall survival (OS)	Up to 2 years
Progression-free survival Rate（1-Y-PFS%, 2-Y-PFS%,3-Y-PFS%）	Up to 3 years
Overall Survival Rate (1-Y-OS%,2-Y-OS%,3-Y-OS%)	Up to 3 years
Objective response rate (ORR)	Up to 2 years
Disease control rate (DCR)	Up to 2 years
Progression-free survival （PFS）	Up to 2 years

Trial Locations

Locations (1)

the First Affiliated Hospital, Zhejiang University School of Medicine; 🇨🇳 Hangzhou, Zhejiang, China