CTNI-13. A FIRST-IN-HUMAN PHASE 0/1 TRIAL OF 5-AMINOLEVULINIC ACID SONODYNAMIC THERAPY (5-ALA SDT) IN RECURRENT GLIOBLASTOMA

Abstract

Abstract BACKGROUND 5-ALA SDT is not a blood-brain barrier disruption technique, but rather a first-in-class drug-device therapy exploiting the heme synthesis pathway in recurrent glioblastoma (rGBM). Following IV 5-ALA administration, aberrant tumor metabolism results in protoporphyrin-IX (PpIX) accumulation. Activation of PpIX by non-invasive, non-ablative magnetic resonance-guided focused ultrasound (MRgFUS) induces reactive oxygen species and tumor cell death. This first-in-human Phase 0/1 study investigates the feasibility, safety, and biological effects of 5-ALA SDT in rGBM patients. METHODS Six hours prior to SDT, adult patients with rGBM were administered 10mg/kg of an IV formulation of 5-ALA (SONALA-001). Patients were assigned to one of three ascending acoustic energy levels of MRgFUS (200J/400J/800J, measured at transducer surface), followed by a four-day interval prior to planned tumor resection. In each patient, 50% of the enhancing and nonenhancing tumor volume was targeted with MRgFUS with the untreated tumor serving as an internal control. The Optimal Biological Dose (OBD) associated with 5-ALA SDT is the energy level associated with greatest tumor cell death. RESULTS 8 patients were accrued across all energy levels, and none demonstrated drug- or device-related adverse events. Compared to internal control tissue, the apoptosis biomarker, cleaved caspase-3, was elevated in all patients, but most prominently at the 200J energy level. The oxidative stress biomarkers 4-hydroxynonenal, glutathione, cysteine, and thiol were elevated in treated vs. control tissues at all energy levels. The mean Cmax for 5-ALA and PpIX in plasma were 305 µM and 65 nM, respectively. No off-target histological or radiographic alterations were detected in any patient. CONCLUSIONS This first-in-human Phase 0/1 study of a new therapeutic modality for rGBM patients demonstrates that 5-ALA SDT is safe at 200 to 800J and likely induces targeted cell death in rGBM patients via oxidative stress. At 10mg/kg of 5-ALA, the OBD is at or lower than 200J.