Investigator-initiated phase I trial of an oligonucleotide therapeutic targeting long noncoding RNA TUG1 for recurrent glioblastoma

Background: Glioblastoma (GB) is considered the most difficult-to-treat primary malignant brain tumor in adults. To date, there is no effective treatment for relapsed GB (rGB). Taurine-upregulated gene 1 (TUG1), a long noncoding RNA highly expressed in GB, resolves R-loop formation and thereby maintains tumor proliferation. TUG1 targeted antisense oligonucleotide (ASO) formulated with a Y-shaped block catiomer (TUG1ASO) is a novel nucleic acid formulation having 18 nm size, which demonstrates pre-clinical efficacy in orthotopic mouse GB models. We are conducting a multicenter Phase I trial to determine the safety and maximum tolerated dose (MTD) of TUG1ASO. Methods: This trial enrolled patients aged 18 to 75 years who relapsed after receiving standard postoperative treatment, chemoradiotherapy with temozolomide. The primary endpoints were the safety and tolerability of TUG1ASO and the MTD. Secondary endpoints included response rate, duration of response, progression-free survival (PFS), overall survival (OS), and pharmacokinetics. The dose escalation was conducted using a 3+3 design, with four dose levels established; level 1=0.1 mg/kg, level 2=0.3 mg/kg, level 3=0.6 mg/kg, and level 4=1.0 mg/kg as the active ingredient for TUG1ASO. Unless discontinuation criteria were met, treatment was administered for 4 cycles, each lasting 7 days, and TUG1ASO administration was permitted until discontinuation criteria were met. The test is currently ongoing, but this report presents the data as December 24, 2025 as the data cutoff date. Results: So far, this trial had enrolled 4 cases at Level 1, 3 cases at Level 2, 6 cases at Level 3, and 3 cases at Level 4. Adverse events leading to delayed administration included 3 cases of leukopenia, 1 case of neutropenia, 6 cases of hypertriglyceridemia, 1 case of increased blood cholesterol, 1 case of hyperuricemia, 1 case of pharyngitis, and 2 cases of cerebral infarction. One case of an allergic reaction led to discontinuation. Among these, hyperuricemia (Level 3), one case of cerebral infarction, and allergic reactions (Level 4) were Grade 3 adverse events and were classified as dose limiting toxicities. All cases showed improvement or recovery. The median mPFS was 54 days (range: 28 to 312 days). Eight cases achieved SD; including one with unconfirmed PR, as the best response. Drug exposure was non-linear beyond dose level 3. Discussion: TUG1ASO is the first nucleic acid therapeutics with a drug delivery system targeting TUG1, and is expected to be effective against GBM. This first-in-human study determined 0.6 mg/kg, as the active ingredient for TUG1ASO, as the maximum tolerated dose (MTD). The treatment has been safely administered up to MTD, with confirmed cases of efficacy. This therapy is expected to lead to the development of new treatments for glioblastoma.