Butaselen combined with radiotherapy for newly diagnosed H3K27M-mutant spinal diffuse midline glioma: A single-arm phase Ib trial.

Abstract

2014 Background: Patients with H3K27M-mutant spinal diffuse midline glioma (sDMG) have a median overall survival (OS) of approximately 13 months and the medical interventions remain limited. Radiation induced senescence (RIS) is a major cause of radiotherapy resistance and tumor recurrence in H3K27M-mutant sDMG. In pre-clinical study, we observe that thioredoxin reductase 1 (TrxR1) protects senescence sDMG cells from oxidative damage caused by radiation, and novel TrxR1 inhibitor Butaselen dramatically induces apoptosis of sDMG cells. Therefore, Butaselen combined radiotherapy is a new strategy to prolong the OS and progression-free survival (PFS) for newly diagnosed H3K27M-mutatnt sDMG patients. Methods: Patients age 18-70 years with newly diagnosed H3K27M-mutant sDMG were eligible for this phase Ib trial (ChiCTR2600116732). All subjects received fixed radiation dose at 45Gy/1.8f/25d. Dose-escalation of Butaselen was performed in phase Ib trial and 9 subjects were enrolled in three dose levels (3+3 design: DL1: 450mg, oral, bid; DL2: 600mg, oral, bid; DL3: 750mg, oral, bid). Butaselen was orally administered in combination with radiotherapy for first 5 weeks, and then administered alone until tumor progression occurs or death. Follow-up visits were conducted at Q8W during 0-6 months and Q12W afterwards. The primary outcome was the safety of the Butaselen, as determined on the basis of adverse events (AEs) and serious adverse events (SAEs). The secondary outcomes were the 12-month OS/PFS rate, OS, PFS, objective response rate (ORR, RANO 2.0 criteria), and objective neurological function scale. Results: Between Apr 18, 2024 and May 21, 2025, 9 eligible subjects were enrolled. 9 subjects (age 26-57 years) received Butaselen therapy with no report of severe adverse event (SAE) or dose-limiting toxicity. As a result, 6-month and 12-month PFS rate (PFS%) was 100% and 88.9% (8/9), respectively, while both 6-month and 12-month OS rate (OS%) reached 100%. The longest PFS has exceed 22 months. 1 subject was died due to disease progress (OS=14.7 month; PFS=6.9 month), 1 subject experienced second operate resecting after disease progress (PFS=12.9 month), and the remaining 7/9 subjects are currently still in the progression-free survival phase. The overall ORR assessed by RANO 2.0 was 33% (3/9) and DCR was 100% (9/9). All subjects (9/9, 100%) experienced the relieve of neurological functions, as measured by Japanese Orthopedic Association (JOA) Scores and McCormick Scores. Grade 3 drug-related treatment-emergent adverse events (TEAEs) occurred 2 times; and no grade 4 TEAEs occurred. Conclusions: Butaselen combined with standard radiotherapy was well tolerated, and exhibited meaningful prolongation of survival period, durable objective responses and neurological function improvements in primary H3K27M-mutant sDMG patients. Clinical trial information: ChiCTR2600116732.