Sonodynamic therapy using MRI-guided focused ultrasound in combination with 5-aminolevulinic acid to treat recurrent glioblastoma multiforme - PROJECT SUMMARY Glioblastoma multiforme (GBM) is a rare and deadly cancer. First line treatment for GBM includes maximal surgical resection with radiotherapy administered post-surgery, and concomitant administration of adjuvant temozolomide. Tumor recurrence is nearly inevitable due to the microscopic, infiltrating cells that are found centimeters from the margin of visible tumor mass. There is currently no effective standard of care for recurrent (rGBM) and this highly aggressive disease leads to death within 15 months after diagnosis and has a 5-year survival rate of <10%. Therefore, there is a clear and significant clinical need for better therapies for rGBM. To address this unmet need, SonALAsense is developing sonodynamic therapy (SDT), a non-invasive drug-device combination, to treat rGBM. SDT uses an MRI-Guided Focused Ultrasound (MRgFUS) device in combination with a drug called 5-aminolevulinic acid (ALA). Three independent laboratories have demonstrated the safety and efficacy of ALA SDT in animal glioma models where the animals were dosed first with ALA and then treated with MRgFUS at energies that do not raise brain temperature. MRgFUS activated Protoporphyrin IX (PpIX), a metabolite of ALA, created singlet oxygen that induced necrosis and apoptosis in the glioma in a process similar to photodynamic therapy. Activation of PpIX non-invasively caused regression of the gliomas and extended survival. A first-in-human Phase 0/1 clinical trial in rGBM showed 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 rGBM only 4 days after treatment. These Phase 0/1 data obtained to date may be interpreted as the successful translation of ALA SDT-treated animal glioma model effects to human rGBM patients. Due to its non-invasive nature, ALA SDT has the unique opportunity to be used multiple times to extend survival. Therefore, a Phase 2 clinical trial will be conducted at 6 clinical trial sites to determine the optimal Phase 2 dosing and schedule to comprehensively evaluate efficacy. This Direct to Phase II project will focus on one clinical trial site at the Ivy Brain Tumor Center. This will be accomplished through the execution of 3 Aims. In Aim 1, we will enroll single patient cohorts to determine maximum tolerated dose and energy for a single dose schedule. In Aim 2, we will determine the recommended schedule by escalating the dosing schedule to 2 then 3 treatments. In Aim 3, we will use the dosing and treatment schedule identified in Aims 1 and 2 to evaluate preliminary efficacy and follow patients weekly in month 1, biweekly in month 2, and monthly thereafter. Completion of this clinical trial will address FDA guidance in our pre-IND meeting and the safety and clinical data from this Phase 2 trial will provide the basis for an end of Phase 2 meeting with the FDA to establish criteria for the approval of ALA SDT as an effective treatment for rGBM. Ultimately, SonALAsense’s ALA SDT combination therapy has great potential to positively impact rGBM patients and their families by improving outcomes.
