Sonodynamic Therapy in Patients With Recurrent GBM

Study Overview
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Brief Summary
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Patients diagnosed with glioblastoma (GBM) are faced with limited treatment options. This pilot study will evaluate the safety and feasibility of combining an investigational drug called 5-ALA with neuronavigation-guided low-intensity focused ultrasound (LIFU) for patients who have recurrent GBM. Focused ultrasound (FUS) can be used to non-invasively destroy tumor tissue while preserving normal tissue. When FUS is combined with 5-ALA, this combinatorial approach is called sonodynamic therapy (SDT), and this investigational therapy is being tested for its ability to cause damage to GBM cells. SDT will take place prior to surgery for recurrent GBM.

Detailed Description
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The combination of 5-ALA (Gleolan) and LIFU is collectively known as sonodynamic therapy (SDT). SDT is an investigational therapy that will be administered 1-3 weeks before surgery for recurrent GBM. Researchers seek to determine the safety and feasibility of this therapy as well as measure its effectiveness to elicit tumor-cell death. All participants are expected to stay overnight in the hospital following administration of SDT to monitor for adverse events.

Official Title
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Pilot Study of Sonodynamic Therapy With 5-ALA for the Treatment of Recurrent Glioblastoma Using Neuronavigation-Guided Low-Intensity Focused Ultrasound

Conditions
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GBM, Recurrent Glioblastoma, Glioblastoma Multiforme

Intervention / Treatment
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* Combination Product: 5-ALA and Low-Intensity Focused Ultrasound (SDT)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Disease status and Disease Parameters: Suspected recurrent glioblastoma that is clearly measurable based on the modified Response Assessment in Neuro-Oncology (RANO) criteria The tumor lesion needs to comprise at least 1 contrast-enhancing lesion with a volume of ≥ 6 cm3 and ≤ 20 cm3 of targeted treatment area Tumor tissue to be treated is in a surgically accessible brain region for biopsy or resection The brain tumor to be treated must be in the treatment envelope of the NaviFUS system (30 mm to 80 mm from the inner skull table) Recurrence will be assessed by imaging and confirmed by consensus at tumor board Men or women between the ages of 18-80 years of age at the time of consent No contraindication to repeat brain surgery Karnofsky Performance Score of 70-100 Able to undergo an MRI with contrast Able to swallow oral medications Willingness and ability to comply with scheduled visits, treatment plans, lifestyle considerations, laboratory tests, and other procedures. Ability to understand and the willingness to sign a written informed consent document (personally or by the legally authorized representative, if applicable). Participants who received prior chemotherapy, radiation therapy, immunotherapy, and/or another investigational therapy must have recovered (Common Terminology Criteria for Adverse Events [CTCAE] Grade ≤1 or baseline) from the acute effects of the therapy or therapies) except for residual alopecia or Grade 2 peripheral neuropathy prior to registration. Has adequate bone marrow and organ function as defined by the following laboratory values (as assessed by the local laboratory for eligibility): Hematological Absolute neutrophil count (ANC) ≥1000/mm3 Platelets ≥ 100,000/mm3 Hemoglobin ≥ 11 g/dL for women and ≥ 12 g/dL for men Participants may receive erythrocyte transfusions to achieve this hemoglobin level at the discretion of the investigator. INR ≤ 1.4 Renal & Hepatic Creatinine clearance CrCl ≥ 60 mL/min/1.73 m2 as estimated by the Cockcroft-Gault (C-G) equation. If estimated CrCl is abnormal, accurate measurement should be obtained by 24- hour CrCl. Bilirubin ≤ 1.5 x ULN (except in patients with Gilbert's disease, where bilirubin to 2.0x ULN is allowed). AST and ALT ≤ 3 x ULN Alkaline phosphatase ≤ 3 x ULN GGT ≤ 3 x ULN Estimated glomerular filtration rate ≥30mL/min/1.73m2 Exclusion Criteria: Known sensitivity or allergy to 5-ALA Simultaneous use of other potentially phototoxic substances (e.g. tetracyclines, sulfonamides, fluoroquinolones, hypericin extracts) Diagnosis of porphyria Hypersensitivity against porphyrins Pregnancy Significant cardiac disease or coagulopathy Herniation / intractable seizure / other clinical indications requiring urgent resection Known active systemic bacterial infection (requiring intravenous [IV] antibiotics at time of initiating study treatment), fungal infection, or detectable viral infection (such as known human immunodeficiency virus positivity or with known active hepatitis B or C (for example, hepatitis B surface antigen positive) Have had a recent (≤3 months prior to registration) transient ischemic attack or stroke Significant vascular disease (e.g. aortic aneurysm) Evidence of bleeding diathesis or coagulopathy Need for systemic anticoagulation which cannot be held for 7 days prior to SDT Unstable angina and/or congestive heart failure (NYH Class III or Class IV; see section 13.2) within 6 months prior to registration Severe hypertension (systolic ≥ 180 mm Hg; diastolic ≥ 120 mm Hg) despite anti-hypertensive medications Transmural myocardial infarction within 6 months prior to registration Serious and inadequately controlled cardiac arrhythmia Acute exacerbation of chronic obstructive pulmonary disease Has serious and/or uncontrolled preexisting medical condition(s) that, in the judgment of the investigator, would preclude participation in this study Treatment with another investigational drug within 30 days prior to registration or within 5 half-lives of the investigational product, whichever is longer Brain edema and/or mass effect that causes midline shift of more than 15 mm Evidence of recent (within 30 days prior to registration) intracranial hemorrhage Calcifications or metallic implanted objects in the focused ultrasound sonication path Scalp atrophy or scars at the expected location of transducer Cerebral or systemic vasculopathy Need for or currently on dialysis Respiratory: chronic pulmonary disorders (e.g., severe emphysema, COPD, pulmonary vasculitis, or other causes of reduced pulmonary vascular cross-sectional area). Receipt of radiotherapy ≤21 days prior to registration Receipt of any of the following ≤ 21 days prior to registration chemotherapy any investigational medications or investigational procedures Prior treatment with sonodynamic therapy Concurrent use of Optune device Concurrent use of supplements or medications with substantial antioxidant effects (including sulfhydryl-containing medications such as captopril or supplements such as N-acetylcysteine, or high doses of vitamins with antioxidant activity such as C or E) Known sensitivity to gadolinium

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sonodynamic Therapy (5-ALA + LIFU)<br>Administration of SDT occurs 1-3 weeks prior to GBM resection | Combination Product: 5-ALA and Low-Intensity Focused Ultrasound (SDT)<br>* 5-ALA (20mg/kg orally) given  6 hours prior to LIFU. Focused ultrasound will target a maximum of 50% of the tumor.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events | Per NCI Common Terminology Criteria for Adverse Events v5.0 | From informed consent through 30 days after study intervention is complete | 
| Severity of adverse events | Per NCI Common Terminology Criteria for Adverse Events v5.0 | From informed consent through 30 days after study intervention is complete | 
| Incidence of intracranial hemorrhage and/or worsening of edema | On post-SDT MRIs | From day after SDT (day 1) up to the time of surgery (day 7-day 21) | 
| Extent of targeted tumor area receiving FUS | Use of NaviFUS system to target a maximum of 50% of the tumor volume of one contiguous lesion | Day 0 | 
| Ability to have participants undergo planned surgery without delay | A delay is defined as more than 3 weeks after SDT | within 3 weeks following SDT | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response of target tissue following SDT on imaging | Via MRI w/ use of modified Response Assessment in Neuro-Oncology (RANO) criteria | From day after SDT (day 1) up to 100 days after intervention is completed | 
| Histologic tumor devitalization | Evaluating cell fate and cell death via histologic samples after GBM resection | Day 7-Day 21 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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5-ALA, Sonodynamic Therapy, Low-Intensity Focused Ultrasound (LIFU), Focused Ultrasound, Brain Cancer