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Sonodynamic Therapy With ExAblate System in Glioblastoma Patients (Sonic ALA)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT04845919
Recruitment Status : Not yet recruiting
First Posted : April 15, 2021
Last Update Posted : April 15, 2021
Information provided by (Responsible Party):
Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta

Tracking Information
First Submitted Date  ICMJE April 2, 2021
First Posted Date  ICMJE April 15, 2021
Last Update Posted Date April 15, 2021
Estimated Study Start Date  ICMJE May 2021
Estimated Primary Completion Date May 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 14, 2021)
Presence of hemorrhage, oedema or other damages [ Time Frame: 10 days after the procedure ]
MR images will be acquired before the procedure and will also be used to guide the FUS treatment; new MRI scans will be acquired at immediately after and at 24 hours, 5 days and 10 days after the procedure and will be analyzed to identify any focal alteration within the treatment's radius compatible with hemorrhages, necrosis, oedema, inflammation or other damages
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (submitted: April 14, 2021)
  • Rate of neurological deficits [ Time Frame: 10 days after the procedure ]
    Patients will be clinically evaluated to identify any change in their clinical picture or new onset of neurological symptoms/deficits,
  • Radiological response to treatment [ Time Frame: 10 days after the procedure ]
    Tumor volume at baseline will be assessed for each patient as gadolinium-enhancing parenchymal regions before any follow-up scan. Post-treatment tumor volumes will be assessed at all follow-up MRI scans, and radiological response to sonodynamic therapy -i.e. the change in pathological volume after the treatment- will be determined by confronting baseline and follow-up scans by the RANO Criteria.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE Sonodynamic Therapy With ExAblate System in Glioblastoma Patients
Official Title  ICMJE A Pilot Study to Evaluate the Safety and Feasibility of Sonodynamic Therapy Using the ExAblate MRI-Guided Focused Ultrasound in the Treatment of Cerebral Glioblastomas.
Brief Summary

The goal of this prospective, non-randomized, single-arm study is to evaluate the safety and feasibility of sonodynamic therapy with 5-aminolevulinic acid in patients with newly diagnosed cerebral glioblastomas using the ExAblate Model 4000 Type-2 "Neuro-System".

Patients will be consented, screened, and will undergo study SDT treatment with 5-ALA using the ExAblate Model 4000 Type-2 "Neuro-System". After SDT treatment, patients will perform a strict neuro-radiological follow-up (minimum of 2 MRI) and undergo tumor resection 14-21 days after SDT, according to the clinical and radiological status.

The main goal of the present study is to investigate the antitumor effects of SDT in patients affected by HGGs attained with low-frequency focused ultrasound.

  • Safety will be evaluated by patient examination and MRI during the treatment, and by follow-up by daily clinical visits and MRI every 3 days. Data on the safety versus adverse effects of this treatment will be acquired during each visit through a combination of MRI evaluations, clinical assessments and neurological examinations.
  • Feasibility will be evaluated performing serial MRI after SDT treatment evaluating tumor size, morphology and peri-lesional edema until tumor resection.

Efficacy is not a primary endpoint. To evaluate the treatment effect, for each subject, the following data will be collected:

  • Tumor volume changes after SDT according to sonicated tumors volumes (by imaging).
  • Histology after tumor resection, comprising assessment of apoptosis and necrosis.
Detailed Description

Despite progress made in many cancer treatments, high-grade gliomas (HGG) remain an extraordinary challenge. Their aggressive and infiltrative nature, the limited efficacy and inherent risk of surgical resection combined with radiotherapy, and the difficulty in delivering anticancer drugs to the brain, make the prognosis for patients with gliomas grim. Therefore, new and less-invasive alternatives to existing procedures are needed.

Sonodynamic therapy (SDT) represents an emerging approach that offers the possibility of non-invasively eradicating solid tumors in a site-directed manner. It involves the delivery of a non-toxic chemical agent that selectively accumulates into target areas and the subsequent exposure of the targeted tissue to relatively low-intensity ultrasound. These procedures (sensitization and ultrasound exposure) are both per se harmless, but, when combined, result in activation of the chemical agent and subsequent cytotoxic events limited to the target tissue volume. SDT offers significant advantages because ultrasound energy can be tightly focused and delivered through the intact skull to deep areas of the brain, depending on the frequency. SDT is achieved by focusing low-intensity and low-frequency ultrasound, which, as opposite to high-intensity ultrasonic beams, can be focused effectively within the whole intracranial space with the currently available device (ExAblate 4000, Insightec, Haifa, Israel). This would enable to target also tumors in the peripheral area of the intracranial space.

5-ALA is a protoporhyrin IX (PpIX) precursor that selectively accumulates in HGGs because of an enhanced uptake and metabolism from tumor cells. It is used for intra-operative guidance in surgery as tumoral tissues shows an exceeding fluorescence under certain light conditions due to PpIX accumulation, as compared to the normal surrounding parenchyma. It is therefore a good candidate for SDT. 5-ALA can exert sonodynamic effects against HGGs, as it has been shown in several pre-clinical studies. Unpublished pre-clinical data on a safety experiment conducted at the University of Virginia showed that SDT with 5-ALA was not exerting a toxic effect to the normal brain.

The idea of the present study is to investigate the antitumor effects of SDT in patients affected by HGGs attained with low-frequency focused ultrasound. Focused ultrasound under MRI-guidance can be safely delivered through an intact human skull to perform SDT in combination with 5-ALA with a low risk of transient adverse effects, as evaluated during follow-up visits, post-procedural serial MRI and histology.

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Other
Condition  ICMJE Glioblastoma Multiforme
Intervention  ICMJE Drug: 5-Aminolevulinic Acid
SDT treatment with 5-ALA using the ExAblate Model 4000 Type-2 "Neuro-System".
Study Arms  ICMJE Experimental: 5-ALA mediated sonodynamic therapy
Intervention: Drug: 5-Aminolevulinic Acid
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: April 14, 2021)
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2022
Estimated Primary Completion Date May 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Suspected primary lobar Glioblastoma clearly measurable on the basis of Response
  • Assessment in Neuro-Oncology (RANO) criteria
  • Brain glioblastomas located in a surgically accessible brain region for resection
  • The targeted tumor resection volume measures between 1cm and 5cm in diameter.
  • Karnofsky rating 70-100
  • American Society of Anesthesiologists (ASA) score 1-3
  • Able to attend all study visits
  • No previous brain surgery
  • No previous radiation treatment
  • No previous systemic treatment for the tumor
  • Able and willing to give informed consent

Exclusion Criteria:

  • Brain glioblastoma presenting with the following characteristics:
  • Brain edema and/or mass effect that causes midline shift of more than 10 mm
  • Evidence of recent intracranial hemorrhage within the targeted tumor volume
  • Calcifications in the focused ultrasound sonication path (system tools may not tailor the treatment around these calcifications)
  • The sonication pathway to the tumor involves either:
  • More than 30% of the skull area traversed by scars, scalp disorders (e.g. eczema),or atrophy of the scalp
  • Clips, shunts, or other metallic implanted objects in the skull or the brain
  • Cardiac disease or unstable hemodynamic status including:

    • Documented myocardial infarction within six months of enrolment
    • Unstable angina on medication
    • Congestive heart failure
    • Left ventricular ejection fraction < 50%
    • Right-to-left, bidirectional, or transient right-to-left cardiac shunts
    • History of a hemodynamically unstable cardiac arrythmia
    • Cardiac pacemaker
    • Severe hypertension
    • Anti-coagulant therapy or medications known to increase risk of hemorrhage within washout period prior to treatment
  • History of a bleeding disorder, coagulopathy or with a history of spontaneous tumor hemorrhage
  • Abnormal level of platelets (<100000) or international normalized ratio (INR) >1.3
  • Cerebral or systemic vasculopathy
  • Known allergy sensitivity or contraindications to gadolinium
  • Contraindications to MRI such as non-MRI-compatible implanted devices
  • Subjects not fitting comfortably into the MRI scanner
  • Difficulty lying supine and still for up to 4 hours in the MRI unit or claustrophobia
  • Positive pregnancy test (for pre-menopausal women)
  • Severely impaired renal function with estimated glomerular filtration rate <30 mL/min/1.73m2 and/or on dialysis
  • Respiratory: chronic pulmonary disorders, e.g. severe emphysema, chronic obstructive pulmonary disease (COPD), pulmonary vasculitis, or other causes of reduced pulmonary vascular cross-sectional area.
  • Any illness or medical condition that in the investigator's opinion precludes participation in this study
  • Patients unable to sign a consent form
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Francesco Prada, MD +39022394 ext 1
Contact: Renato Mantegazza, MD +39022394 ext 2321
Listed Location Countries  ICMJE Not Provided
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT04845919
Other Study ID Numbers  ICMJE Sonic ALA
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta
Study Sponsor  ICMJE Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta
Verification Date April 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP