A Prospective Pivotal Study to Evaluate the Efficacy and Safety of Avastin® Bevacizumab (BEV) With or Without Microbubble-mediated Focused Ultrasound (FUS-MB) Using NaviFUS System in Recurrent Glioblastoma Multiforme Patients

NCT06496971 | Recruiting Phase 3

• 1 other identifier: NF-2023-01
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 2

Brief Summary

This will be a prospective, randomized, standard of care (SoC) controlled, parallel, open-label, multicenter pivotal study to investigate the efficacy and safety of Bevacizumab (BEV) in combination with or without microbubble (MB)-mediated FUS in patients with recurrent GBM. BEV represents the physician's best choice for the standard of care in rGBM after previous treatment with surgery (if appropriate), standard radiotherapy with temozolomide chemotherapy, and with adjuvant temozolomide.

Conditions

Neoplasms; Neoplasms, Nerve Tissue; Brain Tumor; Brain Tumor, Recurrent; Glioblastoma Multiforme; Glioblastoma; Glioblastoma Multiforme, Adult; Glioma

Keywords

NaviFUS System; Blood-Brain Barrier Opening; Focused Ultrasound; FUS; Low-Intensity Focused Ultrasound; LIFU; Bevacizumab; BEV; Avastin

Outcome Measures

Primary Outcomes (1)

• 6-month progression-free survival (PFS-6) of Bevacizumab (BEV) with or without microbubble-mediated focused ultrasound (FUS-MB) using NaviFUS System

  PFS-6 will be estimated the proportion of patients who remain progression-free at the 6-month time point, based on Response Assessment in Neuro-Oncology (RANO) Criteria, from the time of randomization.

  Up to 6 months

Secondary Outcomes (13)

• 12-month progression-free survival (PFS-12)

  Up to 12 months

• Progression-free survival time (PFS)

  Up to 62 weeks

• One- and Two-year survival rates

  Up to 12 and 24 months

• Overall survival (OS)

  Up to 36 months

• Objective response rate (ORR)

  Up to 62 weeks

Study Arms (2)

Standard of care (SoC) BEV alone

ACTIVE COMPARATOR

SoC group will follow the standard operating procedures of BEV (10 mg/kg intravenous (IV) infusion over 30-90 minutes, following the instructions in the drug package insert).

Drug: Bevacizumab

Microbubble-mediated FUS treatment with BEV (FUS-MB+BEV)

EXPERIMENTAL

FUS-MB+BEV group will follow the standard operating procedures of BEV (10 mg/kg intravenous (IV) infusion over 30-90 minutes, following the instructions in the drug package insert). After at least 30 minutes, patients will be administered microbubbles (MB) (SonoVue® ) at a dose of 0.1 mL/kg, along with optimal ultrasound exposure doses determined by the acoustic emission feedback FUS power control algorithm of the NaviFUS System.

Drug: Bevacizumab; Drug: Microbubble; Device: Low-Intensity Focused Ultrasound

Interventions

Bevacizumab DRUG

An anti-angiogenic agent to block tumor growth

Also known as: Avastin

Microbubble-mediated FUS treatment with BEV (FUS-MB+BEV); Standard of care (SoC) BEV alone

Microbubble DRUG

Open the Blood-Brain Barrier (BBB) using focused ultrasound and microbubble

Also known as: SonoVue

Microbubble-mediated FUS treatment with BEV (FUS-MB+BEV)

Low-Intensity Focused Ultrasound DEVICE

Open the Blood-Brain Barrier (BBB) using focused ultrasound and microbubble

Also known as: NaviFUS System

Microbubble-mediated FUS treatment with BEV (FUS-MB+BEV)

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female patients ≥ 18 years of age at the time of study enrollment.
• Body mass index (BMI) ≥ 17 kg/m2.
• Patients diagnosed with glioblastoma must have unequivocal evidence of recurrence, as determined by contrast-enhanced magnetic resonance imaging (CE-MRI), following prior radiotherapy and temozolomide chemotherapy.
• Patients may have undergone surgery for recurrence. The patients should have completed surgery and adequately recovered prior to the time of study enrollment.
• Patients must have radiographic evidence of either at least an 80% resection of enhancing tumor following recurrence or a maximal measurable residual tumor ≤ 20 cm3.
• If patients are receiving corticosteroids, they must have been on a stable or decreasing dose of corticosteroids for at least 1 week prior to the planned first treatment.
• At the time of study enrollment, the minimum interval since the last event:
• weeks out from invasive procedures (e.g., open biopsy, surgical resection, significant traumatic injury, or any other major surgery involving entry into a body cavity) and the patient must have recovered from the effects of surgery
• week out from minor surgical procedures or core biopsies
• Patients must have recovered from the toxic effects of prior therapy at the time of study enrollment as follows:
• weeks out from any investigational drug or device
• weeks out from chemotherapy
• weeks since the completion of a nitrosourea-containing chemotherapy regimen (e.g., Carmustine (BCNU))
• weeks out from completion of radiotherapy
• Patients should have a life expectancy ≥ 12 weeks.

You may not qualify if:

• Patients who have radiographic evidence of multifocal enhancing tumors.
• Patients who have undergone previous treatment with anti-angiogenic therapy, including Bevacizumab, or other VEGF inhibitors or VEGF-receptor signaling inhibitors.
• Patients who have previously received Carmustine wafers implantation during re-operation.
• Patients who have previously received or are currently undergoing tumor treating fields (TTF) treatment.
• Uncontrolled or significant cardiovascular disease, including any of the following:
• New York Heart Association (NYHA) Grade II or above congestive heart failure (CHF) within 12 months prior to study enrollment
• Unstable angina pectoris
• Medical history of myocardial infarction within 6 months prior to study enrollment
• Cardiac shunt
• Stroke (except for transient ischemic attack; TIA) within 6 months prior to study enrollment.
• Patients with implanted electronic device, for example, implanted cardioverter-defibrillator (ICD), cardiac pacemaker, permanent medication pumps, cochlear implants, responsive neurostimulator (RNS), deep brain stimulation (DBS), or other electronic devices implanted in the brain. Patients with contraindications for MRI as judged by Investigator, including non-MRI compatible metallic implant(s).
• Patients with inadequately controlled hypertension, defined as systolic blood pressure \> 150 mmHg and/or diastolic blood pressure \> 100 mmHg while on medication, within 2 weeks prior to first treatment.
• Patients with evidence of any thrombotic or hemorrhagic events, including but not limited to:
• Inherited bleeding diathesis or significant coagulopathy with the risk of bleeding (i.e., in the absence of therapeutic anticoagulation).
• History of pulmonary haemorrhage/haemoptysis ≥ grade 2 according to the CTCAE version 5.0 criteria within 1 month prior to study enrollment

Sponsors & Collaborators

• NaviFUS Corporation: lead

Study Sites (2)

National Taiwan University Hospital

Taipei, 10048, Taiwan

RECRUITING

Linkou Chang Gung Memorial Hospital

Taoyuan District, 33305, Taiwan

RECRUITING

Related Publications (6)

• Chen KT, Tsai HC, Huang CY, Liau CT, Ho KC, Toh CH, Chuang CC, Hsu PW, Huang YC, Chang TW, Yeap MC, Chen PY, Lee CC, Lin YJ, Feng LY, Airan RD, Li G, Lim M, Liu HL, Wei KC. Combination of Neuronavigation-Guided Focused Ultrasound and Bevacizumab for Patients With Recurrent Glioblastoma: A Pilot Study. Neurosurgery. 2025 Nov 24. doi: 10.1227/neu.0000000000003851. Online ahead of print.

  PMID: 41283685 BACKGROUND

• Liu HL, Hua MY, Chen PY, Chu PC, Pan CH, Yang HW, Huang CY, Wang JJ, Yen TC, Wei KC. Blood-brain barrier disruption with focused ultrasound enhances delivery of chemotherapeutic drugs for glioblastoma treatment. Radiology. 2010 May;255(2):415-25. doi: 10.1148/radiol.10090699.

  PMID: 20413754 BACKGROUND

• Wei KC, Chu PC, Wang HY, Huang CY, Chen PY, Tsai HC, Lu YJ, Lee PY, Tseng IC, Feng LY, Hsu PW, Yen TC, Liu HL. Focused ultrasound-induced blood-brain barrier opening to enhance temozolomide delivery for glioblastoma treatment: a preclinical study. PLoS One. 2013;8(3):e58995. doi: 10.1371/journal.pone.0058995. Epub 2013 Mar 19.

  PMID: 23527068 BACKGROUND

• Liu HL, Hsu PH, Lin CY, Huang CW, Chai WY, Chu PC, Huang CY, Chen PY, Yang LY, Kuo JS, Wei KC. Focused Ultrasound Enhances Central Nervous System Delivery of Bevacizumab for Malignant Glioma Treatment. Radiology. 2016 Oct;281(1):99-108. doi: 10.1148/radiol.2016152444. Epub 2016 May 18.

  PMID: 27192459 BACKGROUND

• Chen KT, Lin YJ, Chai WY, Lin CJ, Chen PY, Huang CY, Kuo JS, Liu HL, Wei KC. Neuronavigation-guided focused ultrasound (NaviFUS) for transcranial blood-brain barrier opening in recurrent glioblastoma patients: clinical trial protocol. Ann Transl Med. 2020 Jun;8(11):673. doi: 10.21037/atm-20-344.

  PMID: 32617293 BACKGROUND

• Chen KT, Chai WY, Lin YJ, Lin CJ, Chen PY, Tsai HC, Huang CY, Kuo JS, Liu HL, Wei KC. Neuronavigation-guided focused ultrasound for transcranial blood-brain barrier opening and immunostimulation in brain tumors. Sci Adv. 2021 Feb 5;7(6):eabd0772. doi: 10.1126/sciadv.abd0772. Print 2021 Feb.

  PMID: 33547073 BACKGROUND

Related Links

• Related Info

MeSH Terms

Conditions

Glioblastoma; Glioma; Brain Neoplasms; Neoplasms; Neoplasms, Nerve Tissue

Interventions

Bevacizumab; Microbubbles; contrast agent BR1

Condition Hierarchy (Ancestors)

Astrocytoma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Equipment and Supplies

Central Study Contacts

Sheang-Tze Fung, Ph.D.

CONTACT

02-25860560; stfung@navifus.com

Arthur Lung, Ph.D.

CONTACT

arthur.lung@navifus.com

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Masking Details: Evaluators for radiological response assessment will be blinded to the patient's assigned treatment.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 1, 2024
• First Posted: July 11, 2024
• Study Start: November 8, 2024
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): March 31, 2027
• Last Updated: April 9, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

TW (2)