Phase II clinical study of ACT001 combined with radiotherapy in newly diagnosed pediatric diffuse intrinsic pontine glioma.

2074 Background: Diffuse intrinsic pontine glioma (DIPG) is an extremely lethal type of malignant tumor in the central nervous system of children. Currently, standard radiotherapy has limited efficacy, and there is an urgent need to explore novel therapeutic regimens. This study aims to evaluate the safety and efficacy of ACT001, a novel blood-brain barrier-permeable agent, combined with standard radiotherapy in the treatment of newly diagnosed pediatric DIPG. Methods: This open-label, single-arm, multicenter phase II trial enrolled 5–15-year-old patients with newly diagnosed DIPG. Patients received radiotherapy ( 54 Gy/30 fractions) plus ACT001 (700 mg/m² BID orally, fasting) for 6 weeks (concurrent phase), followed by ACT001 maintenance until progression/toxicity. The primary endpoints were objective response rate (ORR) and overall survival (OS), while the secondary endpoints included progression-free survival (PFS), 1-year OS rate, and safety. Statistical analyses used Kaplan-Meier and Cox regression. Results: A total of 41 patients were screened, with 33 included in the full analysis set (FAS). Thirty-one patients completed the concurrent phase and were included in the per-protocol (PP) set. The median age was 8 years; 18.2% (6 cases) were biopsy-confirmed (83.3% harboring the H3K27M mutation) and 81.8% (27 cases) were radiologically diagnosed. In the FAS, ORR was 30.3% (10 partial responses PR), and the disease control rate was 75.8%; 21.2% (7 cases) in the PP set achieved >50% tumor reduction in pontine lesions. Median OS was 12.7 months (95% CI: 8.7–NA) with a 1-year OS rate of 50.1%; median PFS was 5.9 months (95% CI: 4.3–7.8) with a 6-month PFS rate of 45.3%. Multivariate analysis showed a higher baseline Lansky score was a favorable prognostic factor for OS (HR=0.899, P=0.0069), and achieving PR was favorable for PFS (HR=0.232, P=0.0162). Nineteen patients received salvage therapy post-progression; those undergoing re-irradiation had a median OS of 17.9 months, significantly better than non-re-irradiated patients (P=0.031). Ninety-six point nine percent (32/33) of patients experienced treatment-related AEs (mostly grade 1–2). The incidence of grade ≥3 AEs was 18.2%, with the most common being lymphopenia, weight loss, and upper respiratory tract infection (each 6%). No treatment-related deaths occurred, and no patients discontinued ACT001 due to toxicity. Additionally, 96.9% (31/32) of patients had improved or stable Lansky scores post-treatment. Conclusions: ACT001 combined with standard radiotherapy exhibits certain antitumor activity in the treatment of newly diagnosed pediatric DIPG, with improved OS compared to historical data, as well as a manageable safety profile and good tolerability. This regimen provides a new treatment option for pediatric DIPG and warrants further verification in larger-scale randomized controlled trials. Clinical trial information: ChiCTR2300074598.