Evaluating Bevacizumab with Focused Ultrasound for Recurrent Glioblastoma

A Prospective, Randomized, Standard of Care Controlled, Parallel, Open-Label, Multicenter Pivotal Study to Evaluate the Efficacy and Safety of Avastin® in Combination With NaviFUS System Compared With Avastin® Alone for the Treatment of Recurrent Glioblastoma Multiforme (rGBM)

This study is testing if adding focused ultrasound to the standard treatment of Bevacizumab can help people with recurrent glioblastoma feel better and live longer.

Quick facts

• Phase: Phase 3
• Study type: Interventional
• Enrollment: 32 (estimated)
• Ages: 18 Years to 80 Years
• Sex: All
• Sponsor: NaviFUS Corporation (Industry-sponsored)
• Drugs / interventions: Bevacizumab, chemotherapy
• Locations: 2 sites (Taipei and 1 other locations)
• Trial ID: NCT06496971 on ClinicalTrials.gov

What this trial studies

This study investigates the efficacy and safety of Bevacizumab (BEV) combined with microbubble-mediated focused ultrasound (FUS-MB) in patients with recurrent glioblastoma multiforme (rGBM). It is a randomized, open-label, multicenter trial comparing the standard treatment of BEV alone to BEV combined with FUS-MB. Eligible patients will be randomized in a 1:1 ratio and will receive treatment every two weeks for up to 34 weeks or until disease progression. The study aims to determine if the addition of FUS-MB enhances the effectiveness of BEV in treating rGBM.

Who should consider this trial

Good fit: Ideal candidates are adults aged 18 and older with a confirmed diagnosis of recurrent glioblastoma who have previously undergone surgery, radiotherapy, and temozolomide chemotherapy.

Not a fit: Patients with non-recurrent glioblastoma or those who have not undergone prior standard treatments may not benefit from this study.

Why it matters

Potential benefit: If successful, this approach could improve treatment outcomes for patients with recurrent glioblastoma multiforme.

How similar studies have performed: While focused ultrasound is a novel approach in this context, similar studies have shown promise in enhancing drug delivery across the blood-brain barrier.

Eligibility criteria

Inclusion Criteria:

1. Male or female patients ≥ 18 years of age at the time of study enrollment.
2. Body mass index (BMI) ≥ 17 kg/m2.
3. 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.
4. Patients may have undergone surgery for recurrence. The patients should have completed surgery and adequately recovered prior to the time of study enrollment.
5. 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.
6. 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.
7. At the time of study enrollment, the minimum interval since the last event:

   * 4 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
   * 1 week out from minor surgical procedures or core biopsies
8. Patients must have recovered from the toxic effects of prior therapy at the time of study enrollment as follows:

   * 4 weeks out from any investigational drug or device
   * 4 weeks out from chemotherapy
   * 6 weeks since the completion of a nitrosourea-containing chemotherapy regimen (e.g., Carmustine (BCNU))
   * 12 weeks out from completion of radiotherapy
9. Patients should have a life expectancy ≥ 12 weeks.
10. Patients must have Karnofsky Performance Status (KPS) ≥ 70.
11. Adequate hematopoietic, renal, hepatic, and coagulation function, defined as:

    * Hemoglobin ≥ 10 g/dL
    * Platelets ≥ 100,000/mm3
    * Neutrophils ≥ 1,500/mm3
    * Serum creatinine ≤ 1.5 × upper limit of normal (ULN)
    * Urine protein creatinine ratio (UPCR) \< 1 or urine dipstick for proteinuria ≤ 2+
    * Alanine aminotransferase (ALT) \< 3 × ULN
    * Aspartate aminotransferase (AST) \< 3 × ULN
    * Total bilirubin (TBL) \< 2 × ULN
    * Prothrombin time ≤ 1.5 x ULN
    * International Normalized Ratio (INR) \< 1.5 These tests must be conducted within 2 weeks prior to the planned first treatment.
12. The central of FUS exposure region is located with a minimum distance of at least 30 mm beneath the skull bone.
13. Females of childbearing potential must have a negative pregnancy test documented within 2 weeks prior to first treatment. Females of childbearing potential and male patients with partners of childbearing potential must agree to adhere to an acceptable method of contraception (as outlined below) from prior to the first study treatment until at least 6 months after the completion of last treatment. Standard acceptable methods of contraception include the use of highly effective methods such as hormonal contraception, diaphragm, cervical cap, vaginal sponge, condom, spermicide, vasectomy, intrauterine device, or abstinence from sexual activity.
14. Patients are able and willing to have peripheral intravenous (IV) line placement of Bevacizumab and are able to have hair shaved (either whole head or in the region where the coupling membrane will touch) prior to FUS treatment if assigned to treatment group.
15. Patients or their legal representatives are able to provide written informed consent for participation in the trial and patients are willing to comply the procedures (i.e., study-related assessments), instructions, and restrictions outlined in this study in the duration of the study. Informed consent should also be given for biological materials and diagnostic imaging to be stored and used for future research on brain tumors.

Exclusion Criteria:

1. Patients who have radiographic evidence of multifocal enhancing tumors.
2. Patients who have undergone previous treatment with anti-angiogenic therapy, including Bevacizumab, or other VEGF inhibitors or VEGF-receptor signaling inhibitors.
3. Patients who have previously received Carmustine wafers implantation during re-operation.
4. Patients who have previously received or are currently undergoing tumor treating fields (TTF) treatment.
5. 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
6. Stroke (except for transient ischemic attack; TIA) within 6 months prior to study enrollment.
7. 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).
8. 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.
9. 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
   * Arterial or venous thrombosis (e.g., pulmonary embolism) within 3 months prior to study enrollment
10. Patients with unstable pulmonary disease or chronic obstructive pulmonary disease (COPD) exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of study enrollment.
11. Patients who have psychiatric illness/social situations that would limit compliance with study requirements.
12. Known HIV-positive patient, however, that HIV testing is not required for entry into this study.
13. Acute bacterial or fungal infection requiring intravenous antibiotics at the time of study enrollment.
14. History or evidence of active gastroduodenal ulcer, gastrointestinal perforations/fistula, or intra-abdominal abscess within 6 months prior to study enrollment.
15. Receiving anticoagulant (e.g., warfarin or LMW heparin) or antiplatelet (e.g., aspirin) therapy within 1 week prior to beginning treatment.
16. Known sensitivity/allergy to Magnetic Resonance Imaging (MRI) contrast agents, Computer Tomography (CT) contrast agents, SonoVue®, Bevacizumab, or any of their components.
17. Pregnant (positive pregnancy test) or breast-feeding women.
18. Use of any recreational drugs or history of drug addiction.
19. Other severe concurrent and/or uncontrolled concomitant medical conditions (e.g., active or uncontrolled infection, uncontrolled epilepsy, uncontrolled diabetes) that could cause unacceptable safety risks or compromise compliance with the protocol.
20. Any other condition that, in the Investigator's discretion, might increase the risk to the patients or compromise the evaluation of the clinical trial endpoints.

Where this trial is running

Taipei and 1 other locations

• National Taiwan University Hospital — Taipei, Taiwan (Recruiting)
• Linkou Chang Gung Memorial Hospital — Taoyuan, Taiwan (Recruiting)

Study contacts

• Study coordinator: Sheang-Tze Fung, Ph.D.

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