Resection and intracranial implant of (Z)- <i>n</i> -butylidenephthalide wafer followed by temozolomide as treatment for recurrent glioblastoma: A randomized phase IIb/III trial.

Abstract

TPS2097 Background: Glioblastoma, an isocitrate dehydrogenase (IDH)–wildtype diffuse glioma, remains highly lethal despite standard therapy, and the absence of an effective treatment at recurrence highlights a critical unmet clinical need. (Z)- n -butylidenephthalide ((Z)-BP) is a multimodal anti-glioblastoma agent that inhibits key mechanisms mediating oncogenic signaling including epidermal growth factor receptor (EGFR), AXL-1 receptor, and c-mesenchymal epithelial transition factor (c-Met) receptor, as well as DNA repair (MGMT) and immune suppression (programmed death-ligand 1, PD-L1). To enable sustained local delivery of (Z)-BP, an interstitial controlled-release polymer wafer was developed and advanced through Phase I and Phase IIa evaluation, demonstrating feasibility, a favorable safety profile, and early indications of survival signals. Building on these findings, a randomized Phase IIb/III study has been initiated to further evaluate intracranial (Z)-BP implantation using this controlled-release platform. Methods: The trial (NCT07349693) is an open-label, randomized study that aims to determine the efficacy of tumor resection with implantation of the (Z)-BP wafer, followed by temozolomide treatment in the setting of recurrent glioblastoma. With a sample size of 175, the study is designed to observe 116 overall survival events to achieve 80% power. Eligible adults must have histologically confirmed glioblastoma at first or second recurrence following standard first-line therapy and maintain a Karnofsky Performance Status ≥ 70. Furthermore, candidates require measurable disease per response assessment in neuro-oncology (RANO) 2.0 criteria (lesion ≥ 1 cm) that is deemed suitable for gross total resection. Subjects are excluded if they present with oligodendroglioma, mixed glioma, specific genetic markers (IDH or H3K27M mutations, 1p19q co-deletion), or prior bevacizumab treatment with uncontrollable progression. Patients with MRI findings showing multi-focal disease, diffuse dissemination, lesions &gt; 6 cm, or tumor locations deemed unsuitable for safe resection and wafer implantation will also be excluded. Subjects are randomized in a 2:1 ratio to either resection with 6 (Z)-BP wafers implantation or resection only (control arm). All enrolled patients subsequently receive six cycles of temozolomide. The primary endpoint is median overall survival (OS). Secondary endpoints include progression-free survival (PFS), OS and PFS rates at 6, 9, 12, 18, and 24 months, and objective response rate (ORR, based on RANO 2.0). Exploratory objectives include assessing plasma concentrations of (Z)-BP and its metabolite, quality of life (EORTC QLQ-C30), and survival analyses stratified by molecular subgroups (EGFR, AXL, c-Met, MGMT, and PD-L1 expression). The enrollment is expected in Q2 2026. Clinical trial information: NCT07349693 .