Study to Evaluate 5-ALA Combined With CV01 Delivery of Ultrasound in Recurrent High Grade Glioma

Key Inclusion Criteria

1. Patient must provide informed consent, stating understanding of the procedures andinvestigational nature of the study treatment, and willingness to comply with studyrequirements

2. ≥ 18 years of age

3. WHO performance status of ≤ 2 at screening

4. Part A: Previous histopathologically confirmed diagnosis of high-grade glioma andradiographic evidence of recurrence after prior therapy with radiotherapy. Eligiblehistologies include (according to WHO classification 2021):

5. Astrocytoma, WHO grade 3 and 4 (including subtypes)

6. Oligodendroglioma WHO grade 3 (including subtypes) Parts B and C: Previous histopathologically confirmed diagnosis of glioblastoma andradiographic evidence of recurrence after prior therapy with radiotherapy. WhilePart A may include patients with any type of HGG and any number of recurrences,Parts B and C are restricted to patients with glioblastoma experiencing firstrecurrence.

7. Unifocal or multifocal tumor confined to the supratentorial compartment

8. Interval since last anti-cancer therapy relative to first 5-ALA treatment, asdetailed below

9. End of radiotherapy >12 weeks (including skin-directed radiation for skincancer),

10. Last cytotoxic chemotherapy (4 weeks, if prior nitrosureas 6 weeks).

11. Last biological therapy, i. If bevacizumab ≥ 6 weeks ii. If other monoclonalantibody, e.g., immune checkpoint inhibitor > 3 weeks iii. If tyrosine kinaseinhibitor or other small molecule > 2 weeks

12. Any other investigational agent(s) ≥ 30 days or 5 half-lives, whichever islonger

13. Photodynamic therapy for skin cancer or actinic keratoses ≥ 12 weeks

14. Any toxicity attributable to prior anti-cancer therapy must be resolved to thepatient's baseline level or ≤ Grade 1 (except alopecia).

15. Adequate bone marrow and organ function, defined by the following laboratory values:

16. Absolute neutrophil count (ANC) ≥ 1000 cells/mm3

17. Platelet count ≥ 100,000 cells/mm3

18. Hemoglobin (Hgb) ≥ 8 g/dL

19. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 xupper limit of normal (ULN)

20. Total bilirubin ≤ 1.5 x ULN (unless Gilbert's syndrome, then patients may beeligible if total serum bilirubin is ≤ 3.0 x ULN or direct bilirubin is ≤ 1.5 xULN)

21. Creatinine clearance (CrCL) as estimated by Cockcroft-Gault equation of ≥ 50mL/min

22. Adequate coagulation function defined as PT (prothrombin time)/PTT (partialthromboplastin time) within normal institutional values

23. Males or non-pregnant, non-lactating females who are postmenopausal, surgicallysterile (bilateral tubal ligation with surgery at least 6 weeks prior to studyinitiation or hysterectomy), or who agree to use effective contraceptive methods asdefined by the protocol during the study and for 30 days after the lastinvestigational treatment, see Postmenopausal is defined as at least 12 monthsnatural spontaneous amenorrhea and a serum follicle stimulating hormone (FSH)concentration ≥ 40 IU/L, or at least 6 weeks following surgical menopause (bilateraloophorectomy). a. Women of childbearing potential must have a negative serum human chorionicgonadotropin (hCG) pregnancy test within 7 days prior to first 5-ALA administration

24. Agreement to adhere to Lifestyle Considerations throughout study duration

25. Part C, Surgical group only: Tumor resection surgery is clinically indicated andplanned for the patient, regardless of study participation

Key Exclusion Criteria:

1. Primary infratentorial or brainstem tumors

2. Primary spinal cord tumors

3. Bihemispheric disease (enhancing or non-enhancing) or tumors that involve thebilateral corpus callosum

4. Women who are pregnant or breastfeeding

5. Inability to undergo MRI or receive gadolinium (Gd)-based contrast agents

6. Hypersensitivity to 5-ALA or porphyrins

7. Average skull thickness at the treatment field > 10 mm as assessed by AlpheusMedical. The treatment field is defined as the various locations on the head where thetransducer will be coupled to the patient. The average skull thickness at eachtreatment field will be determined by Alpheus Medical through post-processing thethin cut head computed tomography (CT) (without contrast). The patient's CT scanmust be provided to Alpheus Medical for evaluation as part of the Screening andEnrollment process.

8. Hemorrhagic or ischemic stroke (including transient ischemic attacks) and centralnervous system bleeding in the preceding 6 months that are not related to gliomasurgery. History of prior intratumoral bleeding is not an exclusion criterion;however, patients with a history of prior intratumoral or intracranial bleeding willundergo a non-contrast head CT to exclude acute bleeding.

9. Patients who have clinically significant edema requiring urgent intervention (e.g.,surgery, initiation of steroids, escalating doses of steroids).

10. Patients with progressive and rapid clinical deterioration that, in the opinion ofthe investigator, is likely to worsen during the first cycle of treatment or in theperi-operative interval (in the surgical cohort)

11. Cumulative prior RT dose > 64 Gy

12. Acute or chronic types of porphyria

13. Gastrointestinal disorder that negatively affects absorption

14. Known active hepatitis B or C (Note: testing is not required)

15. Known human immunodeficiency virus (HIV) infection (Note: testing is not required)

16. Unable to avoid phototoxic drugs (e.g., St. John's wort, griseofulvin, thiazidediuretics, sulfonylureas, phenothiazines, sulfonamides, quinolones, andtetracyclines) for 24 hours prior to and following 5-ALA administration

17. Any other concurrent severe or uncontrolled concomitant medical condition that couldcompromise participation in the study (e.g., clinically significant pulmonarydisease, cardiac disease, clinically significant psychiatric or neurologicaldisorder, active or uncontrolled infection)

18. Patient has a condition the Investigator believes would interfere with the abilityto provide informed consent or comply with study instructions, or that mightconfound the interpretation of the study results or put the patient at undue risk