Innv-14. interim report of a phase 1/2 study of sonodynamic therapy (sdt) using aminolevulinic acid (ala) and low-intensity focused ultrasound in pediatric patients with diffuse intrinsic pontine glioma (dipg)

Abstract BACKGROUND DIPGs are devastating pediatric brain tumors with limited treatment options, poor prognosis, and survival of 9-11 months. Preclinical studies demonstrate that performing SDT through MR-guided focused ultrasound (MRgFUS) activates ALA metabolite, protoporphyrin IX (PpIX), leading to tumor cell death and prolonging survival in rodent glioma models through generation of reactive oxygen species and lipoperoxidation, without affecting normal tissue. MEDTHODS: Herein we report preliminary data from an ongoing first-in-child dose-escalation trial of ALA-SDT post-radiation therapy in children ≥ 5 years with DIPG. The trial aims to evaluate the safety and tolerability of ALA-SDT, determine the recommended-phase-2-dose and assess preliminary efficacy and pharmacokinetics (PK) of ALA administered intravenously. RESULTS The first study cohort completed enrollment of 3 subjects. Six hours prior to SDT, patients received an infusion of ALA (SONALA-001) at a dose of 5 mg/kg, followed by sonication with 200J. The first subject was treated in 2 sessions: each to half of the pons 30 days apart. Two subsequent subjects had the entire pons treated in a single session. No dose-limiting toxicity (DLT) or related adverse event 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 a plasma half-life of < 1 hour, indicating rapid distribution (5530 ml/kg). For PpIX, the Cmax occurred 6 hours post-dose and declined with a longer mean half-life of 3.8 hours. Both Cmax and AUCall demonstrate circulating PpIX and systemic exposure were significantly lower than for ALA. CONCLUSION SDT signals an innovative and well-tolerated approach for patients with DIPG in our first study cohort. As expected, the PK for SONALA-001 demonstrate rapid infusion and clearance, whereas for PpIX, the PK are consistent with formation of a metabolite. Clinical trial enrollment is ongoing and dose-escalation cohorts will provide additional PK and safety data.