A FIRST-IN-HUMAN PHASE 0/1 CLINICAL TRIAL OF 5-AMINOLEVULINIC ACID SONODYNAMIC THERAPY IN RECURRENT GLIOBLASTOMA

Abstract 5-Aminoleveulinic acid sonodynamic therapy (5-ALA SDT) is a drug-device strategy that exploits the metabolic liabilities of cancer. Following systemic administration of 5-ALA, aberrant tumor metabolism leads to accumulation of protoporphyrin-IX (PpIX). 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 glioblastoma (GBM) patients. Six hours prior to SDT, adult patients with recurrent GBM are administered Sonala-001 (10mg/kg), an IV formulation of 5-ALA. In a Dose-Escalation Arm, 9-18 patients are assigned to one of three ascending acoustic energy doses of MRgFUS (200J/400J/800J, measured at transducer surface), followed by a four-day interval to planned tumor resection. In each patient, half the tumor volume, including Gadolinium-enhancing and nonenhancing tumor, is targeted with MRgFUS and the other half serves as an internal control. Using tumor pharmacodynamic endpoints, the Minimum Biological Dose (MBD) associated with 5-ALA SDT response is identified. In a subsequent Time-Escalation Arm, 12 patients are treated at the MBD and assigned to one of two time-intervals between SDT and resection. As of May 1, accrual to the 200J dose level (n=3) is complete without significant drug- or device-related adverse events. No cellular or radiographic changes to non-targeted tissue were detected. The median Cmax for 5-ALA and PpIX were 307 µM and 319 nM, respectively. The oxidative stress biomarkers 4-hydroxynonenal, glutathione, cysteine, and thiol were significantly elevated in treated tissue vs. control. Similarly, the apoptosis biomarker cleaved caspase-3 was increased in treated tumor vs. control (median, 48.6% vs. 29.6%, p=0.05). This first-in-human experience with a new therapeutic modality for recurrent glioblastoma patients demonstrates that 5-ALA SDT is safe at 200J. Sonodynamic therapy leads to targeted oxidative stress and tumor cell death in human glioblastoma tissue.