Abstract BACKGROUND 5-ALA sonodynamic therapy is a first-in-class drug-device therapy exploiting the heme synthesis pathway in glioblastoma (GBM). 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 recurrent GBM patients. METHODS In the dose escalation arm of this study, six hours prior to SDT, adult patients with recurrent GBM 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 10 patients were consented and accrued across all energy levels, and none demonstrated drug- or device-related adverse events. In nine evaluable patients, across all energy levels, apoptosis marker, cleaved caspase 3 was elevated accompanied by changes in oxidative stress biomarkers in treated tissue compared to untreated region within the contrast enhancing tumor regions. These effects were modest but pronounced at the lowest energy level Cohort 1 (200J). Two out of three patients in Cohort 1 harbored IDH1 (R132H) mutation. The mean Cmax for 5-ALA and PpIX in plasma were 293 µM and 357 nM, respectively. No off-target histological or radiographic alterations were detected in any patient. CONCLUSION This first-in-human Phase 0/1 study of a new therapeutic modality for recurrent glioblastoma patients demonstrates that 5-ALA SDT is safe at 200 to 800J and likely induces targeted cell death in GBM patients via oxidative stress. Ongoing enrollment in Arms B-E will evaluate the effect of higher dose of 5-ALA and MRgFUS parameters to obtain maximal tumor cell death and evaluate clinical efficacy.
Sanai et al. (Wed,) studied this question.