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

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.

What this study is about