Standard temozolomide plus 5‑ALA and low‑intensity ultrasound after surgery for newly diagnosed glioblastoma

Multi-Center, Randomized, Double-Blind, Placebo-Controlled Trial Comparing Standard of Care Adjuvant Temozolomide With or Without 5-Aminolevulinic Acid (5-ALA) With Concomitant Low Intensity Diffuse Ultrasound (LIDU) Sonodynamic Therapy (SDT) System In Patients With Newly Diagnosed Glioblastoma After Completion of Chemoradiotherapy

This trial tests whether adding the light‑activated drug 5‑ALA together with a low‑intensity ultrasound device to standard temozolomide can help people with newly diagnosed glioblastoma after surgery and chemoradiation.

Quick facts

• Phase: PHASE2
• Study type: Interventional
• Enrollment: 103 (estimated)
• Ages: 18 Years to 80 Years
• Sex: All
• Sponsor: Alpheus Medical, Inc. (industry)
• Drugs / interventions: bevacizumab, chemotherapy, immunotherapy, radiation
• Locations: 8 sites (Boston, Massachusetts and 7 other locations)
• Trial ID: NCT07225621 on ClinicalTrials.gov

What this trial studies

This is a randomized, double‑blind Phase 2 trial that compares an active combination of oral 5‑aminolevulinic acid (5‑ALA) plus a low‑intensity diffuse ultrasound (LIDU) sonodynamic device against placebo plus a sham device in the adjuvant setting. Eligible adults have newly diagnosed, IDH wild‑type glioblastoma who have undergone resection and completed standard concurrent chemoradiation without progression. Participants are randomly assigned to active or placebo/sham arms while all continue standard temozolomide; neither participants nor investigators know the assignment. The goal is to determine whether the investigational drug/device combination can improve outcomes when added to standard therapy.

Who should consider this trial

Good fit: Adults 18–80 with newly diagnosed, IDH wild‑type glioblastoma who have had tumor resection (not biopsy only), completed concurrent chemoradiation with stable disease, and have WHO performance status 0–2 are ideal candidates.

Not a fit: Patients with IDH‑mutant tumors, those who progressed after chemoradiation, biopsy‑only cases, or patients with poor performance status or significant unresolved toxicity are unlikely to benefit from this protocol.

Why it matters

Potential benefit: If successful, the combination could lower recurrence risk or extend progression‑free and possibly overall survival when added to standard temozolomide.

How similar studies have performed: 5‑ALA is well established for fluorescence‑guided surgery but combining 5‑ALA with low‑intensity ultrasound sonodynamic therapy is largely investigational with only limited clinical data so far.

Eligibility criteria

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 \<1.5 x ULN.
10. 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 non-estrogen 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.
11. Women of childbearing potential must have a negative serum human chorionic gonadotropin (hCG) pregnancy test within 7 days prior to first 5-ALA administration
12. 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.
13. No anti-cancer treatment during adjuvant setting after completion of radiation therapy with anything other than temozolomide on Day 2 (+/-1 day) for 5 days per the approved Package Insert (PI).

Exclusion Criteria:

1. Any component of the tumor in the infratentorial location (cerebellar or brainstem tumors are excluded)
2. Bihemispheric disease or tumors that involve the bilateral corpus callosum, or disease burden involving the brain stem or cerebellum based on MRI post-gadolinium enhancement,
3. Multi- centric disease (enhancing or non-enhancing) or multi-focal disease (defined as 2 separate areas of contrast enhancement measuring at least 1 cm that are not contiguous and cannot be encompassed in sonication field on either fluid-attenuated inversion recovery (FLAIR) or T2 hyperintensity.
4. Leptomeningeal disease
5. 6\. A diagnosis of glioscarcoma by histopathology Intent to undergo treatment with the tumor treating fields (TTF) at any time during the study, use prior to screening is permitted.

7\. Corticosteroid use \> 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.

Where this trial is running

Boston, Massachusetts and 7 other locations

• Dana Farber Cancer Institute — Boston, Massachusetts, United States (NOT_YET_RECRUITING)
• Albany Medical Center — Albany, New York, United States (RECRUITING)
• Dent Neurologic Institute — Buffalo, New York, United States (RECRUITING)
• Northwell Health — Long Island City, New York, United States (RECRUITING)
• New York Langone — New York, New York, United States (NOT_YET_RECRUITING)
• Columbia University — New York, New York, United States (RECRUITING)
• University of North Carolina — Chapel Hill, North Carolina, United States (RECRUITING)
• Penn State Milton S. Hershey Medical Center — Hershey, Pennsylvania, United States (RECRUITING)

Study contacts

• Study coordinator: Ann-Marie VP, Clinical Operations

Conditions: Glioblastoma, GBM