Citations

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.

PURPOSE Pharmacologic therapies for neurofibromatosis type 1-associated plexiform neurofibromas (NF1-PNs) are limited; currently, none are US Food and Drug Administration–approved for adults. METHODS ReNeu is an open-label, multicenter, pivotal, phase IIb trial of mirdametinib in 58 adults (≥18 years of age) and 56 children (2 to 17 years of age) with NF1-PN causing significant morbidities. Patients received mirdametinib capsules or tablets for oral suspension (2 mg/m 2 twice daily, maximum 4 mg twice daily), regardless of food intake, in 3 weeks on/1 week off 28-day cycles. The primary end point was confirmed objective response rate (ORR; proportion of patients with a ≥20% reduction of target PN volume from baseline on consecutive scans during the 24-cycle treatment phase) assessed by blinded independent central review (BICR) of volumetric magnetic resonance imaging. RESULTS Twenty-four of 58 adults (41%) and 29 of 56 children (52%) had a BICR-confirmed objective response during the 24-cycle treatment phase; in addition, two adults and one child had confirmed responses during long-term follow-up. Median (range) target PN volumetric best response was –41% (−90 to 13) in adults and –42% (−91 to 48) in children. Both cohorts reported significant and clinically meaningful improvement in patient- or parent proxy-reported outcome measures of worst tumor pain severity, pain interference, and health-related quality of life (HRQOL) that began early and were sustained during treatment. The most commonly reported treatment-related adverse events were dermatitis acneiform, diarrhea, and nausea in adults and dermatitis acneiform, diarrhea, and paronychia in children. CONCLUSION In ReNeu, the largest multicenter NF1-PN trial reported to date, mirdametinib treatment demonstrated significant confirmed ORRs by BICR, deep and durable PN volume reductions, and early, sustained, and clinically meaningful improvement in pain and HRQOL. Mirdametinib was well-tolerated in adults and children.

Abstract Background: Chronic dry eye disease (CDED) is a condition of the ocular surface that causes discomfort, visual disturbance, conjunctival injection, and photophobia. A debilitating form of CDED in patients undergoing allogeneic bone marrow transplant results from ocular graft versus host disease (oGVHD). Autologous serum eye drops (ASED) have beneficial effects on the ocular surface. The aim of this study is to compare improvements in symptoms and function in a cohort of CDED patients with ocular GVHD treated with ASED and a cohort of CDED without GVHD (non-GVHD). We additionally report on some of the biologic characteristics of one specific ASED formulation. Materials and Methods: A total of 71 patients seen in a multi-specialty ophthalmology practice in a university hospital setting receiving ASEDs underwent ocular surface disease index (OSDI) and visual function questionnaire measurements at baseline, 3 months, and 6 months. Twenty-four ASED samples were studied for biomarkers. Results: Compared to baseline, OSDI scores significantly decreased after 3 and 6 months of ASED treatment in both oGVHD and non-GVHD CDED groups. Additionally, visual function questionnaire-25 (VFQ-25) subscales (ocular pain, distance activity, driving, role difficulties, dependency, and mental health) were significantly improved at 3 months and 6 months, and social functioning was improved at 6 months. The majority of patients in both groups had severe disease. Improvements in patient-reported outcomes were greater in the oGHD CDED group than in the non-GVHD CDED group There were no reported complications. Conclusion: ASED is safe and effective in patients with CDED due to oGVHD and non-GVHD. Those with oGVHD had greater improvements. These findings potentiate the wider adoption of this therapy in CDED patients and warrant additional studies into the biochemical makeup of ASED.