FusionVAC22_01: a phase I clinical trial evaluating a DNAJB1-PRKACA fusion transcript-based peptide vaccine combined with immune checkpoint inhibition for fibrolamellar hepatocellular carcinoma and other tumor entities carrying the oncogenic driver fusion.

The DNAJB1-PRKACA fusion transcript was identified as the oncogenic driver of tumor pathogenesis in fibrolamellar hepatocellular carcinoma (FL-HCC), also known as fibrolamellar carcinoma (FLC), as well as in other tumor entities, thus representing a broad target for novel treatment in multiple cancer entities. FL-HCC is a rare primary liver tumor with a 5-year survival rate of only 45%, which typically affects young patients with no underlying primary liver disease. Surgical resection is the only curative treatment option if no metastases are present at diagnosis. There is no standard of care for systemic therapy. Peptide-based vaccines represent a low side-effect approach relying on specific immune recognition of tumor-associated human leucocyte antigen (HLA) presented peptides. The induction (priming) of tumor-specific T-cell responses against neoepitopes derived from gene fusion transcripts by peptide-vaccination combined with expansion of the immune response and optimization of immune function within the tumor microenvironment achieved by immune-checkpoint-inhibition (ICI) has the potential to improve response rates and durability of responses in malignant diseases. The phase I clinical trial FusionVAC22_01 will enroll patients with FL-HCC or other cancer entities carrying the DNAJB1-PRKACA fusion transcript that are locally advanced or metastatic. Two doses of the DNAJB1-PRKACA fusion-based neoepitope vaccine Fusion-VAC-XS15 will be applied subcutaneously (s.c.) with a 4-week interval in combination with the anti-programmed cell death-ligand 1 (PD-L1) antibody atezolizumab starting at day 15 after the first vaccination. Anti-PD-L1 will be applied every 4 weeks until end of the 54-week treatment phase or until disease progression or other reason for study termination. Thereafter, patients will enter a 6 months follow-up period. The clinical trial reported here was approved by the Ethics Committee II of the University of Heidelberg (Medical faculty of Mannheim) and the Paul-Ehrlich-Institute (P-00540). Clinical trial results will be published in peer-reviewed journals. Trial registration numbers: EU CT Number: 2022-502869-17-01 and ClinicalTrials.gov Registry (NCT05937295).

Formulation development of medicated chewing gum tablets by direct compression using the SeDeM-Diagram-Expert-System.

Medicated chewing gums represent an orally administered dosage form with promising potential for local and systemic drug delivery. However, compared to other solid oral dosage forms, formulation development and release mechanism of medicated chewing gums are extremely complex, and thus only few products reached the approval for the market so far. Therefore, Quality by Design (QbD) approaches for rational formulation development of medicated chewing gums are needed to utilize their full potential. For chewing gum tablets, which are manufactured by direct compression, QbD approaches derived from tableting processes might be exerted. In this context, the SeDeM-Diagram-Expert-System implements the QbD approach while indicating whether a blend is suitable for direct compression and comprises powder properties, which need to be improved to facilitate the formulation development. Here, we present the successful application of the SeDeM-Diagram-Expert-System to the formulation development of medicated chewing gum tablets manufactured by direct compression. Furthermore, limitations of the SeDeM-System for medicated chewing gum tablets are evaluated and potential modifications of the system are suggested and discussed for future use.