TIP-03. ADePT A phase I/II study of an AAV-1 mediated dual-payload gene therapy in patients with high grade glioma

Abstract BACKGROUND There have been few advances in glioblastoma treatment in recent decades. Treatments fail due to tumour heterogeneity (genetic, epigenetic, cell-state) and persistence of GBM stem-like cells (GSCs) within the tumour margin. Sox 2 and Sox 9 are consistently overexpressed in GSCs – an exploitable commonality across diverse tumour subtypes. We designed a synthetic superenhancer (SSE), activated by transcription factors known to be highly expressed in GSCs. TGX-007 delivers dual genetic payloads, via AAV-1 mediated delivery, which are activated only in tumour cells under control of this SSE. In our validated immunocompetent mouse model of GBM, TGX-007 administration cures >85% of animals with no associated toxicity and provides immunological memory, preventing tumour formation on re-exposure. METHODS This is a first-in-human, Phase I/II study designed to establish the safety and OBD of TGX-007, and to assess preliminary efficacy in patients with newly-diagnosed GBM or with first radiological progression of previously treated GBM. Tumours must be suitable for ≥90% debulking. TGX-007 is an AAV-1 capsid delivering a transgene encoding HSV-tk and IL12. HSV-tk is an enzyme that converts the nucleoside analogue valaciclovir to a cytotoxic molecule, resulting in cell death. IL-12 is an immune-activating cytokine. TGX-007 will be delivered with intra-operative MRI-guidance via convection enhanced delivery (Clearpoint Smartflow® cannula). Newly-diagnosed patients will first have intra-operative histological confirmation. Patients then receive 2 weeks valaciclovir prior to surgical debulking, then standard care treatment. The study employs a two-stage BOIN12 design to establish the OBD of TGX-007, based on toxicity and signal of activity (HSVtk mRNA in tumour tissue), followed by an expansion for preliminary clinical efficacy evaluation. Primary endpoints are: Phase I - safety and tolerability, OBD determination; Phase II – OS rate at 12 months (newly-diagnosed population) and 6 months (recurrent population). Secondary and exploratory endpoints include PFS, viral shedding, proof-of-mechanism within tumour tissue.