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

Trial Status: Active

This phase I / II trial evaluates the side effects and identifies the best dose of nab-paclitaxel, and checks the feasibility of implanting an ultrasound device, called SonoCloud-9, in treating patients with glioblastoma that has come back (recurrent). A natural sealing of the blood vessels in the brain, called the blood-brain barrier, prevents many drugs carried in the bloodstream from getting into brain tissue. SonoCloud-9 may make the blood brain barrier temporarily more permeable, allowing chemotherapy given into a vein in the arm to better reach the brain tumor. Chemotherapy drugs, such as nab-paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. This trial aims to see whether SonoCloud-9 may improve the effect of nab-paclitaxel on glioblastoma.

Inclusion Criteria

  • Have a histologically confirmed diagnosis of IDH1 wild-type glioblastoma per 2016 World Health Organization (WHO) criteria from the pathology report from surgery that led to diagnosis, that has progressed after standard radiotherapy (RT) and temozolomide with or without tumor treating (TT) fields (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
  • 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 * >= 12 weeks from last dose of last bevacizumab infusion (or other monoclonal antibody therapy)
  • 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
  • If receiving steroids, patient should be on a stable or decreasing dose equivalent to dexamethasone =< 6 mg, for at least 7 days prior to registration
  • 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
  • Have an uncontrolled intercurrent illness
  • 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 thermos-regulation or temperature sensation (due to device)
  • 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

Illinois

Chicago
Northwestern University
Status: ACTIVE
Contact: Adam M. Sonabend
Phone: 312-695-8143

PRIMARY OBJECTIVE:

I. To evaluate the safety and maximum tolerated dose of nab-paclitaxel (albumin-bound paclitaxel) up to a dose of 260 mg/m^2 every (q) 3 weeks (260 mg/m^2 is the recommended and approved dose for other cancers) after pulsed-ultrasound opening of the blood-brain barrier in patients with recurrent glioblastoma. (Phase I)

II. 1-year overall survival rate (calculated from day of surgery for recurrent disease and device implantation). (Phase II)

III. To determine the effect of ultrasound-based blood-brain barrier disruption on peri-tumoral brain and glioma tissue paclitaxel concentrations. (Intraoperative Pharmacokinetic Study)

SECONDARY OBJECTIVE:

I. Feasibility, toxicity and progression-free survival from device implantation. (Phase II)

EXPLORATORY OBJECTIVES:

I. To investigate the extent of tumor and peri-tumoral brain fields covered by pulsed ultrasound blood brain barrier (BBB) disruption by performing gadolinium-enhanced magnetic resonance imaging (MRI) immediately after sonication. (Phase I)

II. Pattern of failure and investigation of whether sonication/microbubbles-based BBB disruption controls tumor growth and prevents local recurrence in field, compared to regions outside the field of sonication.

III. Objective response rate according to Response Assessment in Neuro-Oncology (RANO) criteria.

IV. Measurement of paclitaxel (PTX) concentrations in glioblastoma (GBM) tissue and peri-tumoral human brain following ultrasound (US)-based BBB disruption.

CORRELATIVE OBJECTIVE:

I. To investigate the level of circulating tumor deoxyribonucleic acid (DNA) detected in peripheral blood after US-mediated BBB and correlation with overall survival.

OUTLINE: This is a phase I, dose-escalation study followed by a phase II study.

Patients undergo sonication with SonoCloud-9 implantable ultrasound device during standard of care craniotomy. Within 15 days from surgery, patients receive nab-paclitaxel intravenously (IV) over 30 minutes on day 1. Treatment repeats every 21 days for up to 6 doses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 4 weeks, and then every 2-3 months for up to 1 year.

Trial Phase Phase I/II

Trial Type Treatment

Lead Organization
Northwestern University

Principal Investigator
Adam M. Sonabend

  • Primary ID NU 20C03
  • Secondary IDs NCI-2020-07801, STU00212298
  • Clinicaltrials.gov ID NCT04528680