Abstract
BACKGROUND: Glioblastoma (GB) is the most common and aggressive primary malignant brain tumor in adults. To date, no effective treatment has been reported for recurrent GB (rGB). Long noncoding RNA taurine upregulated gene 1 (TUG1), which is highly expressed in GB, resolves the formation of R-loops, thereby maintaining tumor growth. TUG1-targeting antisense oligonucleotide (ASO) (TUG1ASO) is a nucleotide therapeutic with drug delivery system that targets TUG1, demonstrating efficacy against GB in mouse models. This multicenter, first-in-human, phase I trial aims to investigate the safety and maximum tolerated dose (MTD) of TUG1ASO. METHODS: This study will enroll patients aged 18-75 years with rGB following postoperative temozolomide plus radiation therapy. The primary endpoints will be the safety and tolerability of TUG1ASO and the MTD. The secondary endpoints will be the response rate, duration of response, progression-free survival, overall survival, and pharmacokinetics of TUG1ASO. Dose escalation will be performed utilizing a 3 + 3 design with four dose levels. Unless the discontinuation criteria are met, four cycles will be administered, with each cycle lasting 7 days. Administration of TUG1ASO will be possible until the discontinuation criteria are met. DISCUSSION: TUG1ASO is the first oligonucleotide therapeutic with drug delivery system targeting TUG1, expected to show an efficacy in rGB patients. In this first-in-human study, safety, tolerability and MTD of this new targeted therapy will be confirmed to find the recommended dose for the further clinical trial. This study may contribute to develop a new treatment option for rGB patients. TRIAL REGISTRATION: Japan Registry of Clinical Trials (jRCT) 2041230136, registration date May 17, 2024. REGISTRY: jRCT2041230136. REGISTRATION DATE: May 17, 2024. STUDY DATES: January 1, 2024, to present.