Adjuvant Temozolomide ± 5-Aminolevulinic Acid + Low Intensity Diffuse Ultrasound Sonodynamic Therapy System for Newly Diagnosed Glioblastoma

The purpose of this research is to test an investigational device using ultrasound along with an investigational drug to see if it is useful in treating glioblastoma following standard of care therapy surgery and chemoradiation. This study is evaluating an experimental treatment for glioblastoma that uses an investigational drug (5-ALA) combined with a non-invasive ultrasound device (LIDU) to target tumor cells. Patients meeting the entry requirements to be in the study, will be equally randomly assigned to receive the study device plus the active study drug plus active ultrasound, or to a "sham" procedure where the ultrasound is not being activated and the study drug is a placebo (looks the same but does not contain active drug). Neither the patient or the investigator will know who is in the active group or not. Both groups will continue to receive the standard therapy of oral Temozolomide.

Inclusion Criteria: 1. Patient must provide informed consent, stating understanding of the procedures and investigational nature of the study treatment, and willingness to comply with study requirements 2. ≥ 18 and ≤ 80 years of age 3. WHO performance status of ≤ 2 at screening 4. Newly diagnosed Histologically proven glioblastoma (WHO criteria 2021), absence of IDH mutation demonstrated by negative IDH1 R132H staining on Immunohistochemistry. 5. GBM patients that have an absence of disease progression post craniotomy and TMZ/RT. Note: patients must have undergone prior tumor resection to the extent safely feasible (biopsy only are not eligible). 6. Completion of chemoradiation consisting of radiotherapy (30 x 20 Gy, or equivalent regimen, eg 33 x 18 Gy), with ≥ 90% of the planned radiation therapy dose delivered and concomitant TMZ chemotherapy (75 mg/m2), \>66% of the planned doses administered. 7. Any toxicity attributable to recently completed chemoradiation must be resolved to the patient's baseline level or ≤ Grade 2 (except alopecia or lymphopenia). 8. Adequate bone marrow and organ function, defined by the following laboratory values: A. Absolute neutrophil count (ANC) ≥ 1000 cells/mm3 B. Platelet count ≥ 50,000 cells/mm3 C. Hemoglobin (Hgb) ≥ 8 g/dl D. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 5 x upper limit of normal (ULN) E. Total bilirubin ≤ 3 x ULN (unless gilbert's syndrome, then patients may be eligible if total serum bilirubin is ≤ 5.0 x ULN or direct bilirubin is ≤ 3 x ULN) F. Creatinine clearance (CrCl) as estimated by Cockcroft-Gault equation of ≥ 50 ml/min 9. Adequate coagulation function defined as PT (prothrombin time)/PTT (partial thromboplastin time) defined as either results within normal institutional values or not considered clinically significant \ 4 mg/day of dexamethasone (or equivalent), steroid dose should be stable or decreasing for ≥1 week prior to randomization 8. Inability to undergo MRI or receive gadolinium (Gd)-based contrast agents 9. Hypersensitivity to 5-ALA or porphyrins 10. Patient head size \> 16.6 cm in breadth (max width of head, above the ears) and \> 21.3 cm in length (front to back) to ensure fit within the helmet transducer array. 11. Skull voids/defects \> 10 mm diameter if defect is open, or \> 14 mm if defect is covered with titanium burr hole cover, titanium mesh, or similar repair hardware. Note, Longeviti Neuro Solutions or other sonolucent implants should be treated as open defects and therefore may not exceed 10 mm in diameter. 12. Hemorrhagic or ischemic stroke (including transient ischemic attacks) and central nervous system bleeding in the preceding 6 months that are not related to glioma surgery. History of prior intratumoral bleeding prior to screening is not an exclusion criterion; however, patients with a history of prior intratumoral or intracranial bleeding will undergo a non-contrast head CT to exclude acute bleeding. 13. Has any history of glioma, a concurrent malignancy, or malignancy within 3 years of randomization, unless definitive therapy is completed, with the exception of basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix or breast that has completed curative therapy 14. Patients who have clinically significant cerebral edema requiring urgent intervention (e.g., surgery, initiation of steroids, escalating doses of steroids). 15. Patients with rapid clinical deterioration that, in the opinion of the investigator, is likely to worsen during the first cycle of treatment. 16. Any prior treatment for glioma, aside from surgical resection, and chemoradiation with TMZ. TTF is permitted prior to study entry. Agents used for diagnosis, imaging or visualization, even if investigational, are not exclusionary. Exclusionary treatments would include, but are not limited to: A. Stereotactic radiosurgery B. Placement of Gliadel® (carmustine; BCNU) wafers C. Any other intratumoral or intracavity treatment, D. Receipt of other chemotherapies, bevacizumab, immunotherapy (including vaccine) or investigational agents. 17. Acute or chronic types of porphyria. 18. Gastrointestinal disorder that negatively affects absorption. 19. Known active hepatitis B or C (Note: testing is not required). 20. Known human immunodeficiency virus (HIV) infection (Note: testing is not required). 21. Participation in another interventional clinical trial for GBM. (Observational studies are allowable) 22. Unable to avoid phototoxic drugs (e.g., St. John's wort, griseofulvin, thiazide diuretics, sulfonylureas, phenothiazines, sulfonamides, quinolones, and tetracyclines) for 24 hours prior to and following 5- ALA administration. 23. Any other concurrent severe or uncontrolled concomitant medical condition that could compromise participation in the study (e.g., clinically significant pulmonary disease, cardiac disease, clinically significant psychiatric or neurological disorder, active or uncontrolled infection). 24. Women who are pregnant or breastfeeding 25. Patients with a condition the Investigator believes would interfere with the ability to provide informed consent or comply with study instructions, or that might confound the interpretation of the study results or put the patient at undue risk.