TMZ + RT + 5-ALA + LIDU SDT System for Newly Diagnosed Butterfly Glioma

Prior treatment

• Corticosteroid use \> 4 mg/day of dexamethasone (or equivalent), steroid dose should be stable or decreasing for ≥1 week prior to randomization
• 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.
• 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.
• 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
• Patients who have clinically significant cerebral edema requiring urgent intervention (e.g., surgery, unstable or escalating high doses of steroids).
• 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.
• 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).

Other illness

• Leptomeningeal disease
• Hypersensitivity to 5-ALA or porphyrins
• Gastrointestinal disorder that negatively affects absorption.
• Known active hepatitis B or C (Note: testing is not required).
• Known human immunodeficiency virus (HIV) infection (Note: testing is not required).
• Patients with a condition the Investigator believes would interfere with the ability to comply with study instructions, or that might confound the interpretation of the study results or put the patient at undue risk.

Other

• Any component of the tumor in the infratentorial location (cerebellar or brainstem tumors are excluded)
• Commencing TMZ + RT per SOC before the first SDT treatment
• Inability to undergo MRI or receive gadolinium (Gd)-based contrast agents
• 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.
• Patients with rapid clinical deterioration that, in the opinion of the investigator, is likely to worsen during the first cycle of treatment.
• Acute or chronic types of porphyria.
• Participation in another interventional clinical trial for butterfly glioma/GBM. (Observational studies are allowable)
• Women who are pregnant or breastfeeding

• Patient, or the patient's legally authorized representative, must provide informed consent, stating understanding of the procedures and investigational nature of the study treatment, and willingness to comply with study requirements
• ≥ 18 and ≤ 80 years of age
• WHO performance status of ≤ 2 at screening
• Newly diagnosed histologically proven glioblastoma (WHO criteria 2021), with absence of IDH mutation demonstrated by negative IDH1 R132H staining on immunohistochemistry or equivalent molecular testing.
• Patients must have a radiographic butterfly glioma phenotype on MRI, defined as a contiguous enhancing glioma involving both cerebral hemispheres with midline extension through the corpus callosum (genu, body, and/or splenium) or other commissural pathway. Patients must not have started TMZ/RT. Bilateral involvement must reflect continuous tumor spread across the midline and not merely bilateral edema, mass effect, multifocal non-contiguous disease, or separate bilateral lesions. Note:
  • patients must have undergone prior biopsy or decompressive surgery with histopathologic confirmation of butterfly glioma.
• Adequate bone marrow and organ function, defined by the following laboratory values:
  • Absolute neutrophil count (ANC) ≥ 1000 cells/mm3
  • Platelet count ≥ 50,000 cells/mm3
  • Hemoglobin (Hgb) ≥ 8 g/dL
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x upper limit of normal (ULN)
  • Total bilirubin ≤ 1.5 x ULN (unless gilbert's syndrome, then patients may be eligible if total serum bilirubin is ≤ 3.0 x ULN or direct bilirubin is ≤ 1.5 x ULN)
  • Creatinine clearance (CrCl) as estimated by Cockcroft-Gault equation of ≥ 50 mL/min
• 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 \<1.5 x ULN.
• Non-pregnant, non-lactating females who are postmenopausal, surgically sterile (bilateral tubal ligation with surgery at least 6 weeks prior to study initiation or hysterectomy), or who agree to use effective contraceptive methods as defined by the protocol during the study and for 30 days after the last investigational treatment, see Appendix 1. Postmenopausal is defined as at least 12 months natural spontaneous amenorrhea and a serum follicle stimulating hormone (FSH) concentration ≥ 40 IU/L, or at least 6 weeks following surgical menopause (bilateral oophorectomy). See Appendix 1, females on HRT and whose menopausal status is in doubt will be required to use one of the nonestrogen hormonal highly effective contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of postmenopausal status before study enrollment.
• Women of childbearing potential must have a negative serum human chorionic gonadotropin (hCG) pregnancy test within 7 days prior to first 5-ALA administration
• Male patients must be surgically sterile (i.e., \> 3 months post-vasectomy) or willing to use a highly effective double-barrier contraception method (e.g., male condom with diaphragm or male condom with cervical cap) for the duration of the study and for at least 30 days following SDT treatment. Male patients must not donate sperm from the time of study drug dosing until 30 days following SDT treatment.