Evaluation of DNAJB1-PRKACA Trifluoroacetate Peptide Vaccine in Fibrolamellar Hepatocellular Carcinoma and Oncogenic Driver Fusion Tumors

The primary objective of this clinical trial is to evaluate the **immunogenicity**, safety, and toxicity, as well as the initial efficacy of a DNAJB1-PRKACA fusion transcript-based peptide vaccine, known as Fusion-VAC-XS15. This vaccine is intended for patients with fibrolamellar hepatocellular carcinoma (FL-HCC) or other tumor entities that carry the DNAJB1-PRKACA fusion transcript, serving as an adjuvant treatment. The clinical relevance of this study lies in its potential to provide a novel therapeutic option for these patients, addressing a specific oncogenic driver fusion that is implicated in their disease pathology.

The clinical trial involves participants diagnosed with **fibrolamellar hepatocellular carcinoma** or other tumor entities carrying the oncogenic driver fusion. The study population includes both male and female subjects, with an age range starting from 12 years and no upper age limit specified. Participants are required to have a good general health status, as indicated by an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less. The trial does not include a vulnerable population. The selection criteria emphasize the presence of the DNAJB1-PRKACA fusion transcript and the achievement of complete remission through various therapeutic measures. Participants must have adequate laboratory values and negative tests for hepatitis B, hepatitis C, and HIV. Lifestyle considerations include the requirement for participants to minimize blood and body fluid exposure post-vaccination and adhere to specific contraceptive measures if applicable. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is designed to evaluate the **immunogenicity**, safety, and toxicity of a DNAJB1-PRKACA fusion transcript-based peptide vaccine, Fusion-VAC-XS15, in patients with fibrolamellar hepatocellular carcinoma (FL-HCC) or other tumor entities carrying the oncogenic driver fusion. This is a Phase 1, randomized, double-blind, controlled trial. The trial is expected to commence recruitment on February 3, 2025, and conclude by January 31, 2029. Participants will be involved in the study from the initial screening visit through to the end-of-study (EOS) visit, with the duration of individual participation depending on the study schedule and any unforeseen circumstances that may necessitate early termination.

The sequence of study visits begins with an inclusion (screening) visit, where eligibility is confirmed based on criteria such as age, performance status, and laboratory values. Following successful screening, participants will attend a series of scheduled visits, including the first vaccination visit (V1), where baseline measurements are taken, and the initial dose of the vaccine is administered. Subsequent follow-up visits will monitor the induction of peptide-specific T-cell responses, safety, and any adverse events. The primary endpoints include assessing the immunogenicity and safety of the vaccine, while secondary endpoints focus on the percentage of patients with T-cell response induction, disease control rate, progression-free survival, overall survival, and quality of life scores.

Participants are expected to adhere to specific conditions, such as using effective contraception and refraining from blood donation, to remain in the study. Early termination may occur due to adverse events, non-compliance, or withdrawal of consent. The trial's design ensures that data collection and analysis are conducted in a scientifically rigorous manner, adhering to the Common Terminology Criteria for Adverse Events (CTCAE V 5.0) for safety assessments. The study aims to provide valuable insights into the potential of Fusion-VAC-XS15 as an adjuvant treatment for FL-HCC and related tumor entities.

The clinical trial involves the administration of an experimental medication, **Fusion-VAC-XS15**, which is an emulsion for injection. The active substance in this formulation is **DNAJB1-PRKACA trifluoracetate**, a protein-based compound. The medication is administered via subcutaneous injection. The dosing schedule and frequency of administration are determined by the study protocol, although specific details are not provided in the available data. The formulation is not a pediatric formulation and is not classified as an orphan drug. The product is developed by the University Hospital Tuebingen.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are mentioned. The focus is solely on evaluating the immunogenicity, safety, toxicity, and initial efficacy of the **Fusion-VAC-XS15** vaccine in patients with fibrolamellar hepatocellular carcinoma or other tumors carrying the DNAJB1-PRKACA fusion transcript. Participant compliance with the dosing schedule is monitored as per the clinical trial protocol, although specific compliance measures are not detailed in the provided information.

The clinical trial aims to evaluate the efficacy of the DNAJB1-PRKACA fusion transcript-based peptide vaccine, Fusion-VAC-XS15, in patients with fibrolamellar hepatocellular carcinoma (FL-HCC) or other tumor entities carrying the oncogenic driver fusion. Efficacy will be primarily assessed by measuring the **immunogenicity** of the vaccine, specifically the induction of peptide-specific T-cell responses. This will be evaluated using the IFNγ ELISPOT assay at each scheduled visit until the end-of-study (EOS) visit, compared to baseline measurements taken prior to the first vaccination.

Secondary efficacy endpoints include the percentage of patients with induced peptide-specific T-cell responses, the disease control rate (complete response, partial response, stable disease) assessed by RECIST1.1 at each visit, progression-free survival (PFS) from the date of first vaccination until disease progression or death, and overall survival (OS) from the date of first vaccination until death from any cause. Additionally, overall quality of life scores will be measured using the EORTC QLQ C-30 at every scheduled visit until the EOS visit. The trial will also monitor the number and percentage of patients receiving or scheduled to receive a booster vaccination, as well as the incidence and severity of adverse events, including adverse events of special interest, serious adverse events, and suspected unexpected serious adverse reactions, from the first vaccination until the EOS visit.