Safety of BBB Disruption Using NaviFUS System in Recurrent Glioblastoma Multiforme (GBM) Patients

A FIH Feasibility Study to Evaluate the Safety of Transient Disruption of Blood-brain Barrier in Recurrent Glioblastoma Multiforme (GBM) Patients Using NaviFUS System

This study is to evaluate the safety and find the tolerated ultrasound dose of transient opening of the blood-brain barrier (BBB) by using the NaviFUS System in recurrent GBM patients.

This is a feasibility, open-label, single-arm, and dose escalation study. Eligible patients will be enrolled through the process of informed consent. Patients will be assigned into different dose groups generated from the NaviFUS System to transiently open the BBB in patients with recurrent GBM who will undergo surgery within 2 weeks. The focused ultrasound (FUS) dose is selected based on the results of pre-clinical Good Laboratory Practice (GLP) safety studies as well as other non-GLP primate studies. This study will evaluate the safety and the tolerated ultrasound dose of temporary disruption of the BBB in patients with recurrent GBM. To find the tolerated ultrasound dose, the data and safety monitoring board (DSMB) will review the study data and provide the recommendations regarding continuation, termination, or other modifications of the study based on evaluation of observed adverse effects of the intervention. The extent and magnitude of BBB opening will be evaluated using of dynamic contrast-enhanced MRI (DCE-MRI).

Inclusion Criteria:

• Patients diagnosed with recurrent GBM and will undergo surgery

• Able to give written informed consent for the participation in the trial

• Adult male/female patients > 20 years of age

• Patients if already on radiotherapy, a gap of 7 days shall be maintained between the last day of radiotherapy and the day of screening

• Patients if already on the steroids treatment, then should be on a stable dose of steroids for at least 7 days prior to screening

• Body mass index (BMI) ≥17 kg / m2

• Patients with life expectancy ≥ 3 months

• Able to comply with study requirements in the opinion of the investigator

• Adequate hepatic, renal, coagulation, and hematopoietic function

  • Hemoglobin ≥ 10 g/dL
  • Platelets ≥ 100,000/mm3
  • Neutrophils ≥ 1,500/mm3
  • Normal creatinine clearance ≥ 50mL/min
  • Alanine transaminase (ALT) < 3 x upper limit of normal (ULN)
  • Aspartate transaminase (AST) < 3 x ULN
  • Prothrombin time ≤ 1.2 x ULN
  • International Normalized Ratio (INR) < 1.5
  • Bilirubin < 2 x ULN

• Patients with the ROI for FUS exposure are located close to the cortex with at least 20 mm distance beneath the skull bone and the ROI is not in the deep center brain with crucial brain functions, such as in the region of brain stem, or motor or speech regions

• The Karnofsky performance status (KPS) in the patient must be > 60

Exclusion Criteria:

• Patients at screening visit have arteriovenous malformation (AVM) or cerebral aneurysm
• Use of any recreational drugs or history of drug addiction
• Pregnant or breast-feeding women
• The receipt of an investigational drug, or participation in a drug research study within a period of one month prior to the first FUS exposure
• Known sensitivity/allergy to MRI contrast agents, CT contrast agents, SonoVue®, or any of its components
• Any other condition that, in the investigator's judgment, might increase the risk to the patients or decrease the chance of obtaining satisfactory data needed to achieve the objectives of the study
• Abnormal baseline findings considered by the investigator to indicate conditions that might affect study endpoints
• Patients who have hemorrhage or cyst within the ROI
• Severe hypertension at screening (diastolic blood pressure > 100 mmHg on medication)
• Receiving anticoagulant (e.g. warfarin) or antiplatelet (e.g. aspirin) therapy within one week prior to study treatment or drugs known to increase risk or hemorrhage (e.g. Avastin) within one month prior to study treatment