PD-1 mRNA LNP Vaccine for Advanced Primary Hepatocellular Carcinoma.

Official title

A Prospective，Single Arm Clinicial Trial Evaluating PD-1 mRNA LNP Vaccine for the Treatment of Advanced Primary Hepatocellular Carcinoma Failing Standard Therapy

Overview

Evaluating the Safety and Efficacy of PD-1 mRNA LNP Vaccine Therapy in Patients with Primary Hepatocellular Carcinoma Who Have Failed Advanced Standard Therapy

Detailed description

PD-1 mRNA LNP is an immune checkpoint mRNA vaccine loaded with the gene coding for the PD-1 protein Safety, tolerability, immunogenicity and preliminary efficacy of mRNA vaccines with PD-1 as the immunogen in the treatment of primary liver cancer. The aim of this study is to establish a novel PD-1-based mRNA for the treatment of advanced cancers.

Interventions

• Drug Low Dose PD-1 mRNA LNP Vaccine
  Patients will receive PD-1 mRNA LNP vaccine at 50 mcg weekly for the first 4 doses and a 5th dose 1 month after the 4th dose.
• Drug High dose PD-1 mRNA LNP vaccines
  Patients will receive PD-1 mRNA LNP vaccine at 100 mcg weekly for the first 4 doses and a 5th dose 1 month after the 4th dose.

Primary outcome measures

• Adverse events [Time frame: One month after the first vaccine dose]

Secondary outcome measures (7)

• Disease Control Rate (DCR) [Time frame: Two month after the first vaccine dose]
• DRR (Durable Response Rate) [Time frame: Six month after the first vaccine dose]
• DOR (Duration of Response) [Time frame: Six month after the first vaccine dose]
• TTR (Response Time） [Time frame: Six month after the first vaccine dose]
• PFS (progression-free survival) [Time frame: Six month after the first vaccine dose]
• OS (Overall Survival) [Time frame: Six month after the first vaccine dose]
• TTP (Time to Progression) [Time frame: up to 6 months]

Eligibility criteria

Inclusion criteria

• Male or female patients: ≥18 years of age; ≤70 years of age;
• Recurrent or metastatic hepatocellular carcinoma that has failed second-line standard therapy.
• Patients with at least one target lesion with a measurable diameter according to the RECIST criteria (CT scan of tumor lesions with a long diameter of ≥10mm, CT scan of lymph node lesions with a short diameter of ≥10mm and a layer thickness of no more than 5mm);
• ECOG physical condition score: 0 to 1;
• Expected survival ≥ 3 months;
• Good function of major organs, i.e., relevant examination indexes within 14 days prior to randomization meet the following requirements:

• Routine blood tests: hemoglobin ≥80g/L (no blood transfusion within 14 days); neutrophil count >1.5×109 /L; platelet count ≥80×109 /L;
• Biochemical tests: total bilirubin ≤1.5 × ULN (upper limit of normal); blood alanine aminotransferase (ALT) or blood alanine transaminase (AST) ≤ 2.5 × ULN; if liver metastases, ALT or AST ≤ 5 × ULN; endogenous creatinine clearance ≥ 60 ml/min (Cockcroft-Gault formula);
• cardiac Doppler ultrasound: left ventricular ejection fraction (LVEF) (LVEF) ≥50%.
• Good compliance and family agreement to cooperate in receiving survival follow-up.

Exclusion criteria

• Participation in a clinical trial of another drug within 4 weeks;
• Patients with a prior history of other neoplasms, unless cervical cancer in situ, treated squamous skin cancer or epithelial tumor of the bladder or other malignancies that have undergone radical therapy (at least 5 years prior to enrollment);
• Patients with uncontrolled cardiac clinical symptoms or disease, such as NYHA class 2 or higher heart failure, unstable angina pectoris , myocardial infarction within 1 year, clinically significant Supraventricular or ventricular arrhythmias requiring treatment or intervention.
• For female subjects: women who are pregnant or breastfeeding.
• Patients with active tuberculosis, bacterial or fungal infection (≥ grade 2 of NCI-CTCAE 5.0); HIV infection; active HBV infection; HCV infection.
• Those with a history of psychotropic substance abuse that they are unable to abstain from or those with mental disorders;
• Subjects with any active autoimmune disease or history of autoimmune disease (e.g., the following, but not limited to : uveitis, enteritis, pituitary gland inflammation, nephritis, hyperthyroidism, hypothyroidism; subjects with vitiligo or asthma that has resolved completely in childhood and does not require any intervention in adulthood may be enrolled; subjects with asthma requiring medical intervention with bronchodilators may not be enrolled).
• Patients who have been inoculated with mRNA drugs.
• Participation in clinical trials involving lipid nanoparticles, a component of the study vaccine.
• Contraindications to intramuscular injection.
• History of substance abuse or known medical, psychological or social conditions such as alcohol or drug abuse.
• Known allergy, hypersensitivity or intolerance to the investigational vaccine (including any excipients). Previous history of severe allergy to any drug, food, or vaccination, such as anaphylaxis, allergic laryngeal edema, allergic dyspnea, anaphylactic purpura, thrombocytopenic purpura, localized anaphylactic necrotic reaction (Arthus reaction).
• The female subject is planning to become pregnant or the male subject's partner is planning to become pregnant during the Screening Period and up to 12 months after the full course of drug administration.
• In the judgment of the investigator, there is a serious concomitant disease that jeopardizes the patient's safety or interferes with the patient's ability to complete the study.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

China · 2 centers

• West China Hospital, Sichuan University — Chengdu
• Sichuan University West China Hospital — Chengdu

Publications

• Chen X, Wu Y, Yang T, Wei M, Wang Y, Deng X, Shen C, Li W, Zhang H, Xu W, Gou L, Zeng Y, Zhang Y, Wang Z, Yang J. Salidroside alleviates cachexia symptoms in mouse models of cancer cachexia via activating mTOR signalling. J Cachexia Sarcopenia Muscle. 2016 May;7(2):225-32. doi: 10.1002/jcsm.12054. Epub 2016 Jan 18. PMID 27493875
• Wu Y, Li W, Chen X, Wang H, Su S, Xu Y, Deng X, Yang T, Wei M, Li L, Liu Y, Yang J, Li W. DOG1 as a novel antibody-drug conjugate target for the treatment of multiple gastrointestinal tumors and liver metastasis. Front Immunol. 2023 Jan 26;14:1051506. doi: 10.3389/fimmu.2023.1051506. eCollection 2023. PMID 36776873
• Sabnis S, Kumarasinghe ES, Salerno T, Mihai C, Ketova T, Senn JJ, Lynn A, Bulychev A, McFadyen I, Chan J, Almarsson O, Stanton MG, Benenato KE. A Novel Amino Lipid Series for mRNA Delivery: Improved Endosomal Escape and Sustained Pharmacology and Safety in Non-human Primates. Mol Ther. 2018 Jun 6;26(6):1509-1519. doi: 10.1016/j.ymthe.2018.03.010. Epub 2018 Mar 14. PMID 29653760
• Selvaggio G, Leonardelli L, Lofano G, Fresnay S, Parolo S, Medini D, Siena E, Marchetti L. A quantitative systems pharmacology approach to support mRNA vaccine development and optimization. CPT Pharmacometrics Syst Pharmacol. 2021 Dec;10(12):1448-1451. doi: 10.1002/psp4.12721. Epub 2021 Oct 21. No abstract available. PMID 34672423
• Xu S, Yang K, Li R, Zhang L. mRNA Vaccine Era-Mechanisms, Drug Platform and Clinical Prospection. Int J Mol Sci. 2020 Sep 9;21(18):6582. doi: 10.3390/ijms21186582. PMID 32916818
• Linares-Fernandez S, Lacroix C, Exposito JY, Verrier B. Tailoring mRNA Vaccine to Balance Innate/Adaptive Immune Response. Trends Mol Med. 2020 Mar;26(3):311-323. doi: 10.1016/j.molmed.2019.10.002. Epub 2019 Nov 5. PMID 31699497
• Verbeke R, Hogan MJ, Lore K, Pardi N. Innate immune mechanisms of mRNA vaccines. Immunity. 2022 Nov 8;55(11):1993-2005. doi: 10.1016/j.immuni.2022.10.014. PMID 36351374
• Lim SA, Cox A, Tung M, Chung EJ. Clinical progress of nanomedicine-based RNA therapies. Bioact Mater. 2021 Oct 22;12:203-213. doi: 10.1016/j.bioactmat.2021.10.018. eCollection 2022 Jun. PMID 35310381

Identifiers

NCT: NCT07053072 · 2025-755

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗