Safety and Efficacy of Bevacizumab in Combination With NaviFUS System for the Treatment of Recurrent Glioblastoma Multiforme (rGBM)

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), followingprior radiotherapy and temozolomide chemotherapy.

4. Patients may have undergone surgery for recurrence. The patients should havecompleted surgery and adequately recovered prior to the time of study enrollment.

5. Patients must have radiographic evidence of either at least an 80% resection ofenhancing tumor following recurrence or a maximal measurable residual tumor ≤ 20cm3.

6. If patients are receiving corticosteroids, they must have been on a stable ordecreasing dose of corticosteroids for at least 1 week prior to the planned firsttreatment.

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 abody 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 ofstudy 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 close to the cortex, with a minimumdistance of at least 30 mm beneath the skull bone.

13. Females of childbearing potential must have a negative pregnancy test documentedwithin 2 weeks prior to first treatment. Females of childbearing potential and malepatients with partners of childbearing potential must agree to adhere to anacceptable method of contraception (as outlined below) from prior to the first studytreatment until at least 6 months after the completion of last treatment. Standardacceptable methods of contraception include the use of highly effective methods suchas 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 ofBevacizumab and are able to have hair shaved (either whole head or in the regionwhere the coupling membrane will touch) prior to FUS treatment.

15. Patients or their legal representatives are able to provide written informed consentfor participation in the trial and patients are willing to comply the procedures (i.e., study-related assessments), instructions, and restrictions outlined in thisstudy in the duration of the study.

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 signalinginhibitors.

3. Patients who have previously received Carmustine wafers implantation duringre-operation.

4. Patients who have previously received or are currently undergoing tumor treatingfields (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 studyenrollment

• Cardiac shunt

6. Stroke (except for transient ischemic attack; TIA) within 6 months prior to studyenrollment

7. Patients with implanted electronic device, for example, implantedcardioverter-defibrillator (ICD), cardiac pacemaker, permanent medication pumps,cochlear implants, responsive neurostimulator (RNS), deep brain stimulation (DBS),or other electronic devices implanted in the brain.

8. Patients with inadequately controlled hypertension, defined as systolic bloodpressure > 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 notlimited to:

• Inherited bleeding diathesis or significant coagulopathy with the risk ofbleeding (i.e., in the absence of therapeutic anticoagulation).

• History of pulmonary haemorrhage/haemoptysis ≥ grade 2 according to the CTCAEversion 5.0 criteria within 1 month prior to study enrollment.

• Arterial or venous thrombosis (e.g., pulmonary embolism) within 6 months priorto study enrollment.

10. Patients with unstable pulmonary disease or chronic obstructive pulmonary disease (COPD) exacerbation or other respiratory illness requiring hospitalization orprecluding study therapy at the time of study enrollment.

11. Patients who have psychiatric illness/social situations that would limit compliancewith study requirements.

12. Know HIV-positive patient, however, that HIV testing is not required for entry intothis study.

13. Acute bacterial or fungal infection requiring intravenous antibiotics at the time ofstudy enrollment.

14. History or evidence of active gastroduodenal ulcer, gastrointestinalperforations/fistula, or intra-abdominal abscess within 6 months prior to studyenrollment.

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, Lumason® , Avastin® , or any of theircomponents.

17. Pregnant (positive pregnancy test) or breast-feeding women.

18. Use of any recreational drugs or history of drug addiction.

19. Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g.,active or uncontrolled infection, uncontrolled epilepsy, uncontrolled diabetes) thatcould cause unacceptable safety risks or compromise compliance with the protocol.

20. Any other condition that, in the Investigator's discretion, might increase the riskto the patients or compromise the evaluation of the clinical trial endpoints.