Liver Cancer
Conditions
Brief summary
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
DRUGLow 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.
DRUGHigh 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.
Sponsors
West China Hospital
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This single-centre, open-label, single-arm trial uses a dose-escalation framework to evaluate the safety and biological activity of PD-1 mRNA LNP in the treatment of patients with advanced hepatocellular carcinoma who have failed standard therapy. All participants will maintain a fixed chemotherapy/immunotherapy regimen based on their respective malignancies, with only the dose of PD-1 mRNA LNP changing. Three cases will be enrolled in each dose group, with the planned dose groups being the 50 μg and 100 μg groups. It consisted of 5 doses of basal immunisation and subsequent personalised treatment. For the base immunisation, the first 4 doses were administered 1 week apart each and the 5th dose was administered 1 month after the 4th dose. Dose-limiting toxicity (DLT) will be monitored through a 21-day monitoring window. Escalation decisions will be made using a Bayesian Optimal Interval (BOIN) approach, with DLT classification following the
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. Male or female patients: ≥18 years of age; ≤70 years of age; 2. Recurrent or metastatic hepatocellular carcinoma that has failed second-line standard therapy. 3. 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); 4. ECOG physical condition score: 0 to 1; 5. Expected survival ≥ 3 months; 6. 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%. 7. Good compliance and family agreement to cooperate in receiving survival follow-up.
Exclusion criteria
1. Participation in a clinical trial of another drug within 4 weeks; 2. 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); 3. 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. 4. For female subjects: women who are pregnant or breastfeeding. 5. Patients with active tuberculosis, bacterial or fungal infection (≥ grade 2 of NCI-CTCAE 5.0); HIV infection; active HBV infection; HCV infection. 6. Those with a history of psychotropic substance abuse that they are unable to abstain from or those with mental disorders; 7. 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). 8. Patients who have been inoculated with mRNA drugs. 9. Participation in clinical trials involving lipid nanoparticles, a component of the study vaccine. 10. Contraindications to intramuscular injection. 11. History of substance abuse or known medical, psychological or social conditions such as alcohol or drug abuse. 12. 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). 13. 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. 14. 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Adverse events | One month after the first vaccine dose | Adverse events defined as the number of participants with adverse events |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease Control Rate (DCR) | Two month after the first vaccine dose | The ratio of subjects assessed with CR or PR or stable disease (SD) as a best overalresponse. |
| DRR (Durable Response Rate) | Six month after the first vaccine dose | DRR is defined as the proportion of objective response (CR and PR as determined by the investigator) lasting at least 6 months at any time within 12 months of initiation of treatment. |
| DOR (Duration of Response) | Six month after the first vaccine dose | DOR is defined as the time from the date when the PR is first recorded or better to the date when the disease progression is first recorded (for the responder, i.e., PR or better). Responders who did not record disease progress will be censored on the date that the last assessment was SD or better. |
| TTR (Response Time） | Six month after the first vaccine dose | TTR is defined as the time from the date of the first administration to the date of the first record of the objective tumor response (CR and PR determined by the investigator). |
| PFS (progression-free survival) | Six month after the first vaccine dose | PFS is defined as the duration until disease progression or death in participants fromthe first dose of immunization. |
| OS (Overall Survival) | Six month after the first vaccine dose | 0S is defined as the duration until death in participants from the first dose ofimmunization. |
| TTP (Time to Progression) | up to 6 months | TTP is defined as the time from the date of first dose to the date of first documented disease progression, as defined by standard disease criteria. |
Countries
China
Contacts
CONTACTXingchen Peng
PRINCIPAL_INVESTIGATORXingchen Peng
West China Hospital
Outcome results
None listed