Ctni-33. A Pivotal Phase Iib/Iii Study for a Localized Glioblastoma Treatment Targeting Receptor Tyrosine Kinase Defined Network

Localized delivery of therapeutics for glioblastoma offers key advantages, including bypassing the blood-brain barrier, reducing systemic toxicity, and enabling targeted surgical placement. A biodegradable wafer containing the anti-glioblastoma agent Z-n-butylidenephthalide (Z-BP), known as the Z-BP wafer, has been developed and optimized for this purpose. Here we report pre-clinical and phase I/IIa clinical data for Z-BP Wafer and the design of a phase IIb/III study. GSEA-based RNAseq of patient-derived glioblastoma lines before and post-Z-BP treatment, canine pharmacokinetic studies, and results of a phase I/IIa trial of recurrent glioblastoma patients. Pre-clinical analysis of glioblastoma response to Z-BP revealed regulation of key nodes in a receptor tyrosine kinase (RTK) defined network, including mammalian target of rapamycin (mTOR), 5′−AMP−activated protein kinase (AMPK) signaling pathway, and DNA repair pathways. Accordingly, glioblastoma cell lines with RTK hyperactivation were more sensitive to Z-BP. Pharmacodynamic studies using canine models showed that the highly hydrophobic Z-BP diffused > 2 centimeters from a single wafer implantation, achieving therapeutic concentrations. Minimal Z-BP (< 0.05 μM) were detected in the serum or the cerebrospinal fluid of Z-BP wafer-treated canines. In the phase I/IIa trial, patients treated with the Z-BP wafer experienced limited adverse reactions, with no adverse events of grade ≥ 3 attributable to the wafer implant. The median overall survival (mOS) of the GBM patient treated with 6 wafers was 15.7 months. Among treated patients, those whose tumors with RTK over-expression showed a mOS of 26.2 months, compared to 2.5 months in patients without such expression. Notably, the quality of life of Z-BP treated patients improved as a function of increasing wafer implanted. Pre-clinical and phase I/IIa clinical trials suggest potential for Z-BP as a therapeutic platform for glioblastoma. A multi-national, randomized phase IIb/III clinical trial is scheduled to commence in the fourth quarter of 2025.