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 .

Abstract BACKGROUND Children with DIPG have limited treatment options and poor prognosis with median survival of 9-12 months. Preclinical studies reveal that sonodynamic therapy (SDT) via MR-guided focused ultrasound (MRgFUS) activates SONALA-001 (ALA) metabolite, protoporphyrin IX (PpIX), inducing tumor cell death and extending survival in glioma models. METHODS We present preliminary data from an ongoing first-in-child drug-device trial (NCT05123534) of SONALA-001 SDT in children with DIPG aged ≥ 5 years post-radiation therapy. The trial evaluates the safety of ALA-SDT, preliminary efficacy and pharmacokinetics (PK) of SONALA-001 at 5mg/kg administered 6-12 hours before SDT and establishes the RP2D. Each cohort involves three subjects: the first receiving half-pons treatment 30-days apart; the others receiving entire pons treatment. Single-treatment approach was amended to allow up to 12 monthly-treatments. RESULTS Six patients (4M:2F, 5-12 years) in 2 cohorts received 22 SDT-treatments between August 2022 and February 2023. Sonication duration averaged 147 minutes. Five of 6 patients received repeated treatments. All were discharged post-procedure day 1 with no DLTs or related AE grade ≥ 3. For SONALA-001, the Cmax occurred at end of infusion, followed by rapid clearance (15.7 mL/min/kg); plasma half-life of < 1 hour, indicating rapid distribution. The PpIX-Cmax occurred 4-6 hours post-dose, declining 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 6 patients achieved a partial response per RAPNO central-review, and 2 continue in the study treatment for 11 and 15 months, respectively. CONCLUSION SDT is an innovative and to-date well-tolerated strategy for children with DIPG post-initial radiotherapy. Sonications did not result in any adverse procedural effects. SONALA-001 exhibits rapid distribution and clearance, while PpIX PK align with metabolite formation. After dose escalation completion, dose-expansion at R2PD will offer insights into safety, PK, and efficacy.

Abstract Diffuse intrinsic pontine glioma (DIPG) is the leading cause of mortality amongst pediatric neuro-oncologic diseases. Sonodynamic therapy with non-ablative MR-guided focused ultrasound (MRgFUS) is being investigated in multiple clinical trials. We describe safety outcomes and initial efficacy of SDT with 5-ALA for the treatment of pediatric patients with DIPG. Twelve patients with DIPG were treated from August 2022-April 2024 as part of a dose-escalation protocol with SDT in a multicenter Phase 1/2 clinical trial (NCT05123534). MRgFUS was combined with the prodrug SONALA-001 (5-ALA iv) to activate its metabolite, protoporphyrin IX, and thereby induce apoptosis within tumor cells. Treatment is delivered every 4 weeks for up to 12 treatments. Patient ages ranged from 3-23 years and 60% were male. Twelve patients underwent a total of 45 SDT treatments (range 2-9). When enrolled, median tumor volume was 1,337 cm3 (range, 310-2078 cm3) and duration since diagnosis was 5 months. SONALA-001 doses tested were 5 mg/kg and 10 mg/kg. Delivered ultrasonic acoustic energy ranged from 190-444 joules/cm3. After 6 months of median follow-up (range 2-18), 2 partial responses occurred, and 9 of 12 patients had stable or improved baseline symptoms (Lansky Status), including improved mobility and diplopia. One adverse clinical event included a small non-operative epidural hematoma secondary to a stereotactic frame pin. There have been no grade 3 or worse treatment-related adverse events or dose-limiting toxicities. Ten patients are alive a median of 11 months after diagnosis; 2 have deceased; 4 have discontinued treatment. Maximum percent tumor volume changes throughout treatment ranged from a -68% reduction to over 100% enlargement. Preliminary analysis of twelve pediatric patients treated with SDT for DIPG demonstrates acceptable safety outcomes and promising clinical results. Additional patient enrollment and longer follow-up times are required to determine efficacy.

TPS2101 Background: Recurrent glioblastoma (rGBM) is a lethal brain tumor with no effective therapy and an extremely poor prognosis (median survival 6 to 8 months after first recurrence). Sonodynamic therapy (SDT) is a non-invasive combination treatment that utilizes a drug, aminolevulinic acid HCL (SONALA-001), and a device, the Exablate 4000 Type 2.0, to deliver non-ablative MR-guided focused ultrasound (MRgFUS) to tumor. Preclinical studies have shown that SDT-induced sonoluminescence activates protoporphyrin IX (PpIX), which in turn generates reactive oxygen species that lead to tumor cell death and improved survival in animal glioma models. A first-in-human Phase 0 trial (NCT04559685) indicated that SONALA-001 SDT was well-tolerated and not associated with off-target cellular or radiographic effects, and provided direct evidence of reactive oxygen species formation and targeted tumor cell death in recurrent high-grade glioma (rHGG). Methods: SDT-202 is a Phase 1/2 multicenter, open-label, dose escalation and expansion study (NCT05370508) of 10 mg/kg iv SONALA-001 in combination with MRgFUS for SDT in patients with progressive or recurrent GBM. Treatments take place every 4 weeks. In phase 1, sonication energy escalation utilizes an accelerated titration design with a single subject for dose level 1, followed by cohorts 2 and 3 with 3+3 design for additional dose escalation. SONALA-001 is administered 6 to 12 hours prior to MRgFUS treatment. Once the RP2D is determined, Phase 2 dose expansion will enroll approximately 36 additional subjects to assess safety and efficacy of repeated cycles of SONALA-001 SDT at the optimized RP2D. Endpoints of this study are safety evaluation, maximum tolerated dose (MTD), recommended Phase 2 dose (RP2D), and determination of pharmacokinetic (PK) parameters. The Phase 2 portion will further characterize safety of RP2D along with evaluation of efficacy with PFS6 (mRANO), ORR, CBR, DOR, DOCR, TTR, and OS. Clinical trial information: NCT05370508 .

Abstract Recurrent glioblastoma (rGBM) is a lethal brain tumor with no effective standard of care option and an extremely poor prognosis (median survival 6 to 8 months after first recurrence). Sonodynamic therapy (SDT) is a non-invasive combination therapy that utilizes a drug, aminolevulinic acid HCL (SONALA-001, ALA), and a device, the Exablate 4000 Type 2.0 to deliver MR-guided focused ultrasound (MRgFUS). Preclinical studies have shown that SDT activates protoporphyrin IX (PpIX) to generate reactive oxygen species that lead to tumor cell death and improved survival in animal glioma models. A first-in-human Phase 0 trial (NCT04559685) indicated that ALA SDT was well-tolerated and not associated with off-target cellular or radiographic effects and provided direct evidence of reactive oxygen species formation and targeted tumor cell death in recurrent high-grade glioma (rHGG). SDT-202 is a Phase 1/2 multicenter, open-label, dose escalation and expansion study (NCT05370508) of iv SONALA-001 (ALA) in combination with MRgFUS for SDT in patients with progressive or recurrent GBM. Dose escalation will include an initial drug and energy dose escalation of ALA SDT utilizing an accelerated titration design with single subject cohorts for dose level cohorts 1 and 2, followed by cohort 3 with 3 + 3 design for additional dose escalation. SONALA-001 is administered 6 to 9 hours prior to MRgFUS treatment. Once the RP2D is determined, Phase 2 dose expansion will enroll approximately 36 additional subjects to assess safety and efficacy of repeated cycles of ALA SDT at the optimized RP2D. Endpoints of this study are safety evaluation, maximum tolerated dose (MTD), recommended Phase 2 dose (RP2D), and determination of pharmacokinetic (PK) parameters. The Phase 2 portion will further characterize safety of RP2D along with evaluation of efficacy with PFS6 (mRANO), ORR, CBR, DOR, DOCR, TTR, and OS. Preliminary PK and safety results will be presented.

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.

TPS10070 Background: Diffuse intrinsic pontine glioma (DIPG) is a devastating pediatric brain tumor with poor prognosis. Sonodynamic therapy (SDT) with ALA is a non-invasive strategy that sensitizes target tissues with a non-toxic chemical agent followed by exposure to low intensity MR-guided focused ultrasound (MRgFUS). Preclinical studies have shown that ALA is preferentially taken up by glioma cells and metabolized to protoporphyrin IX (PpIX). SDT activates protoporphyrin IX and induces tumor cell death via photodynamic effect (lipoperoxidation, apoptosis). Suheiro et al and Wu et al demonstrated that SDT killed tumors via apoptosis and lipoperoxidation in rodent glioma models with minimal damage to surrounding normal brain. 1,2 ALA SDT was well-tolerated in an ongoing first-in-human trial in adults with recurrent high-grade gliomas and demonstrated biomarker evidence of the photodynamic effect 3 . Methods: A Phase 1/2, multicenter, open label study (NCT05123534) is enrolling patients at Children’s National Hospital. The study employs the Bayesian optimal interval (BOIN) algorithm to evaluate safety and tolerability of treatment with SDT in newly diagnosed DIPG subjects to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of MRgFUS energy in combination with ALA. The study will evaluate 3 ALA doses and 3 acoustic energy doses. ALA is administered IV six to nine hours prior to MRgFUS with the Exablate type-2 device. The first cohort, B1C1, evaluates the lowest drug-device dose combination and if no dose-limiting toxicity (DLT) is encountered after 3 patients, ascending dose-escalation will proceed to the second cohort, B2C1, treated with lowest dose of ALA with the second level of MRgFUS energy. Again, if no DLT is experienced, the next cohort will receive a higher dose combination. The initial patient in each cohort is treated in 2 sessions 21 to 28 days apart, each covering one-half of the pons. Subsequent patients are treated in 1 session to the whole pons. The primary objective is to evaluate the safety and tolerability of SDT in DIPG subjects. Secondary outcomes include preliminary efficacy assessments, pharmacokinetics of ALA and PpIX, mechanical performance of the Exablate Type-2 device, and radiographic evidence of tumor physiological changes associated with SDT. All patients at least 5 years of age with newly diagnosed, radiographically typical DIPG between 4-24 weeks after completion of standard radiotherapy are eligible for the trial. Patients with evidence of disease progression, diagnosis of porphyria, or prior or concurrent therapy with any other anticancer or investigational intervention will be excluded. Cohort 1 has been completed without DLT. References: 1. Suheiro et al. J Neurosurg 2018;129:1416-1428. 2. Wu et al. Sci Rep 2019;9:10465. 3. Sanai et al. NeuroOnco 2022;24(&):vii72-vii73. Clinical trial information: NCT05123534 .

Objective MR-guided focused ultrasound (MRgFUS) is increasingly being used to treat patients with essential tremor (ET) and Parkinson's disease (PD) with thalamotomy and pallidotomy, respectively. Pallidotomy is performed off-center within the cranium compared to thalamotomy and may present challenges to therapeutic lesioning due to this location. However, the impact of target location on treatment efficiency and ability to create therapeutic lesions has not been studied. This study aimed to compare the physical efficiency of MRgFUS thalamotomy and pallidotomy. Methods Treatment characteristics were compared between patients treated with thalamotomy (n = 20) or pallidotomy (n = 20), matched by skull density ratios (SDR). Aspects of treatment efficiency were compared between these groups. Demographic and comparative statistics were conducted to assess these differences. Acoustic field simulations were performed to compare and validate the simulated temperature profile for VIM and GPi ablation. Results Lower SDR values were associated with greater energy requirement for thalamotomy (R2 = 0.197, p = 0.049) and pallidotomy (R2 = 0.342, p = 0.007). The impact of low SDR on efficiency reduction was greater for pallidotomy, approaching significance (p = 0.061). A nearly two-fold increase in energy was needed to reach 50°C in pallidotomy (10.9kJ) than in thalamotomy (5.7kJ), (p = 0.002). Despite lower energy requirement, the maximum average temperature reached was higher in thalamotomy (56.7°C) than in pallidotomy (55.0°C), (p = 0.017). Mean incident angle of acoustic beams was lesser in thalamotomy (12.7°) than in pallidotomy (18.6°), (p < 0.001). For all patients, a lesser mean incident angle correlated with a higher maximum average temperature reached (R2 = 0.124, p = 0.026), and less energy needed to reach 50°C (R2=0.134, p = 0.020). Greater skull thickness was associated with a higher maximum energy for a single sonication for thalamotomy (R2 = 0.206, p = 0.045) and pallidotomy (R2 = 0.403, p = 0.003). An acoustic and temperature field simulation validated similar findings for thalamotomy and pallidotomy in a single patient. Conclusion The centrally located VIM offers a more efficient location for therapeutic lesioning compared to GPi pallidotomy in SDR matched cohort of patients. The impact on therapeutic lesioning with lower SDR may be greater for pallidotomy patients. As newer off-center targets are investigated, these findings can inform patient selection and treatment requirements for lesion production.

PURPOSE:During magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy for refractory tremor, high temperatures must be achieved and sustained for tissue necrosis. We assessed the impact of both patient-specific as well as procedure-related factors on the efficiency of acoustic energy transfer, or heating efficiency (HE). METHODS:Retrospective analysis of 92 consecutive patients (857 sonications) with essential tremor or tremor-dominant Parkinson's disease treated at a single institution. Temperature elevations at the target were measured for each sonication with MR thermometry. HE of each sonication was defined as the ratio of peak temperature elevation and the delivered energy. HE was analyzed with respect to patient skull features (area, thickness, skull density ratio [SDR]), computed from CT scans, as well as demographic and clinical variables (age, sex, diagnosis, and duration of symptoms). RESULTS:Across the full range of sonication energies that can be delivered with current devices (up to 36 kJ), average sonication HE was diminished in patients with lower SDR. In individual subjects, there was a progressive loss in HE as sonication energy was titrated up throughout the course of treatment, with a more rapid decline in patients with higher SDR. This energy-dependent loss in HE was not related to procedural factors, namely, the number of previous sonications, or the cumulative energy deposited during previous sonications. In contrast to SDR, neither skull area nor thickness was an independent predictor of average HE or the rate of its decline with increasing energies. In 11% of patients, all of whom with SDR < 0.45, sonication HE fell below the threshold to reach 54°C even with delivery of maximum energy. In contrast, temperatures ≥ 50°C could be obtained in all but one patient. CONCLUSIONS:SDR is predictive of sonication HE, and determines patient-specific limits on the magnitude of temperature elevation that can be achieved with current devices. These data inform strategies for predictable lesioning in MRgFUS thalamotomy.