Blood-Brain Barrier Opening with the SonoCloud-9 Implantable Ultrasound Device, Nab-Paclitaxel and Carboplatin for the Treatment of Recurrent Glioblastoma

Inclusion Criteria

• Have a histologically confirmed diagnosis of IDH1 (R132H) wild-type glioblastoma per 2016 WHO criteria or the revised 2021 WHO classification, i.e.. * Grade 4 astrocytoma, absence if IDH mutation and/or; * Molecular features of glioblastoma, e.g., any of these features a) EGFR amplification, b) gain chrs 7 and loss chrs 10, c) TERT promoter mutation
• Disease has progressed after a standard or investigational first-line therapy (e.g. radiotherapy (RT), RT plus temozolomide) with or without TTFields. Patients who have received fractionated first-line radiation therapy and no prior chemotherapy (e.g. as common practice for MGMT unmethylated tumors), or who have participated in an investigational protocol substituting TMZ for a novel agent are eligible. (Note: pathology of the resected tumor will be reviewed by our expert reference neuropathologist, for trial inclusion we will rely on the previously established local diagnosis of a GBM.)
• Be able to undergo contrast-enhanced magnetic resonance imaging (MRI)
• Have radiographic evidence of tumor progression with measurable (>= 1 cm) or evaluable disease by contrast-enhancement on MRI, according to RANO criteria * Measurable: contrast-enhancement of bidirectional diameters >= 1 cm * Evaluable disease is defined as tumor that can be seen on MRI, that due to small size or irregular shape cannot be measured in a reproducible way * Note: Inclusion of subjects at University of California San Francisco (UCSF) will require review of screening MRI by Northwestern team for eligibility
• Maximal tumor diameter at inclusion (pre-surgery) =< 70 mm on T1wMRI
• Candidate for surgical resection for disease recurrence or progression
• Interval since completion of radiotherapy > 12 weeks, unless there is tissue confirmation of tumor recurrence or progression outside the radiation treatment field. Prior treatment with radiosurgery or other high-dose focused radiation is acceptable, but the patient must have subsequent histologic documentation of recurrence, unless the recurrence occurs remote to the treated site
• Interval since last cytotoxic therapy until presumed date of surgery >= 1 cycle or >= 2 biological half-lives, i.e. * >= 4 weeks since last dose of temozolomide * >= 6 weeks since last dose of lomustine or other nitrosourea * >= 3 weeks since last dose of a small molecule targeted agent * >= 6 weeks from last dose of last bevacizumab infusion
• Ability to understand patient information and written informed consent and has provided signed and dated informed consent prior to study registration and study related procedures
• Age >= 18 years
• If receiving dexamethasone for mass effect, a stable daily dose of dexamethasone at < 6 mg within 7 days of registration, or if dexamethasone dose is decreasing, average daily dose of < 6 mg in the 7 days prior to registration. Patients on dexamethasone for reasons other than mass effect may still be enrolled
• WHO performance status =< 2 (corresponding to a Karnofsky performance status [KPS] of >= 70)
• No signs of peripheral neuropathy or neuropathy =< grade 1
• Hemoglobin >= 9.0 g/dL (within 14 days prior to registration)
• Leukocytes >= 3,000/L (within 14 days prior to registration)
• Absolute neutrophil count >= 1,500/L (within 14 days prior to registration)
• Platelets >= 100,000/l (within 14 days prior to registration)
• Total bilirubin < 1.5 mg/dL (within 14 days prior to registration)
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SPGT]) =< 3 X institutional upper limit of normal (ULN) (within 14 days prior to registration)
• Creatinine =< 1.5 mg/dL (within 14 days prior to registration)
• Have a negative pregnancy test within 14 days prior to registration on study (for female of child-bearing potential [FOCBP])
• Agree to use adequate contraception: * (e.g. hormonal or barrier method of birth control; abstinence) if a female of child-bearing potential (FOCBP) or a male, prior to study entry, for the duration of study participation, and for 30 days following completion of therapy. Should a female patient become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately * NOTE: A FOCBP is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria: * Has not undergone a hysterectomy or bilateral oophorectomy * Has had menses at any time in the preceding 12 consecutive months (and therefore has not been naturally postmenopausal for > 12 months)

Exclusion Criteria

• Have multifocal tumor (unless all localized in a 70-mm diameter area accessible to ultrasound field) or tumor located in the posterior fossa
• Are at increased risk of wound dehiscence (e.g. 3 or more previous craniotomies, brain surgery within the last 3 months, poor skin condition, and/or previously infected surgical field or any other condition that is of increased infectious risk in the opinion of the neurosurgeon)
• Have uncontrolled epilepsy
• Require treatment with enzyme-inducing antiepileptic drugs
• Have clinical evidence of peripheral neuropathy on examination > grade 1
• Have received any other investigational agents within 4 weeks of registration
• Have received prior therapy with or have history of allergic reactions attributed to compounds of similar chemical or biologic composition to paclitaxel or carboplatin
• Hypertension grade 3 or higher without adequate control on medications
• Ongoing or active infection requiring systemic treatment
• Symptomatic congestive heart failure
• Unstable angina pectoris
• Unstable cardiac arrhythmia
• Pneumonitis
• Psychiatric illness/social situations that would limit compliance with study requirements
• Any other illness or condition that the treating investigator feels would interfere with study compliance or would compromise the patient’s safety or study endpoints
• Patients with coils, clips, shunts, intravascular stents, and/or non-removable wafer, non-resorbable dura substitute, or reservoirs
• Patients with medical need to continue antiplatelet therapy
• Patients with known significant cardiac disease, known to have right-to-left shunts, severe pulmonary hypertension (pulmonary artery pressure > 90 mmHg), uncontrolled systemic hypertension, or adult respiratory distress syndrome. (patient at risk for microbubble reaction)
• Patients with impaired thermo-regulation or temperature sensation
• Are pregnant or nursing
• Patients with a history of active malignancy within 3 years prior to registration. Note: Exceptions to this requirement include adequately treated non-melanoma skin cancer or lentigo maligna or carcinoma in situ without evidence of disease, or intraoperative proof that lesion to be operated is indeed recurrent glioblastoma
• Known history of hypersensitivity reactions to: * Perflutren lipid microsphere components or to any of the inactive ingredients in Definity (European brand name: Luminity) microbubbles products * Fluorescein (Fluorescite) and other ingredients in this product