Abstract
2067 Background: Children with DIPG have limited treatment options and a poor prognosis, with median survival of 9-12 months. Preclinical studies reveal that sonodynamic therapy (SDT) with MR-guided focused ultrasound (MRgFUS) activates ALA metabolite, protoporphyrin IX (PpIX), leading to tumor cell death and extending survival in glioma models. Methods: SDT-201 (NCT05123534) is a multi-center, first-in-child dose escalation trial of SDT with SONALA-001 and MRgFUS administered in children aged ≥ 5 years with DIPG, enrolled 4-20 weeks post-radiation therapy and prior to disease progression. The trial evaluates the safety and preliminary efficacy of SDT and pharmacokinetics (PK) of intravenous ALA (SONALA-001) at 5mg/kg, administered 6-12 hours before MRgFUS to the pons (delivered to half the pons 30 days apart for the first patient in each cohort of 3, with subsequent patients receiving entire pons treatment). The trial was subsequently amended to allow up to 12 monthly treatments. Results: Six patients in 2 cohorts were treated (4 male:2 female, range 5-12 years) between August 2022 and December 2023. No DLTs or related AE grade ≥ 3 were observed. For SONALA-001, the Cmax occurred at the end of infusion, followed by rapid clearance (15.7 mL/min/kg) with plasma half-life of < 1 hour, indicating rapid distribution. The PpIX Cmax occurred 4-6 hours post-dose and declined with a longer mean half-life than SONALA-001 of 6 hours. Both Cmax and AUCall demonstrate circulating-PpIX and systemic exposure were significantly lower than for SONALA-001. Two of the first 6 patients achieved a partial response per RAPNO central-review, and 2 subjects continuing treatment are 11 to 15 months from start of study therapy. Conclusions: SDT is a well-tolerated strategy for patients with DIPG after initial radiotherapy. SONALA-001 shows rapid distribution and clearance, and PpIX PK align with metabolite formation. Following dose escalation completion, dose-expansion will be initiated at RP2D offering further insights into safety, PK, and efficacy. Clinical trial information: NCT05123534 .
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