Ultrasound-based Blood-brain Barrier Opening and Albumin-bound Paclitaxel and Carboplatin for Recurrent Glioblastoma

NCT04528680 | Active Not Recruiting Phase 1 DMC FDA Drug FDA Device

• 1 other identifier: NU 20C03
• Study Type: interventional
• Target: 57
• Locations: 1 country
• Sites: 1

Brief Summary

Paclitaxel is among the most active agents against glioblastoma in preclinical models. However, its clinical use has been hampered by the blood-brain barrier (BBB). In this trial we will implant a novel device with 9 ultrasound emitters allowing to temporarily and reversibly open the BBB immediately prior to chemotherapy infusion with albumin-bound paclitaxel. In the phase 1 component, increasing doses of chemotherapy will be delivered as long deemed safe based on the prior patient not experiencing severe toxicity. Once the the recommended dosing has been established, carboplatin will be added to the regimen and additional patients will be treated in order to better evaluate the antitumor efficacy of this novel treatment. The device will be implanted at the time of surgical resection of the recurrent tumor. During that procedure and when feasible, a first test dose of the chemotherapy will be administered in the operating room after sonication (procedure of activating ultrasound and opening the BBB) and tissue concentrations in different parts of the resected tumor will be measured. In select patients, the sonication procedure may occur immediately after the test dose of chemotherapy is administered. The objectives of this trial are to establish a safe and effective dose of albumin-bound paclitaxel, to demonstrate that the opening of the BBB increases chemotherapy concentration in the tumor, and to estimate how effective this treatment is in reducing the tumor burden and prolonging life.

Conditions

Glioblastoma; Gliosarcoma; GBM; Glioblastoma Multiforme; Glioblastoma, IDH-wildtype; Recurrent Glioblastoma

Keywords

ultrasound; SonoCloud; blood-brain barrier; paclitaxel; albumin-bound paclitaxel; Abraxane®; carboplatin

Outcome Measures

Primary Outcomes (3)

• Dose limiting toxicity (Phase1)

  Occurrence of ≥ grade 3 treatment related toxicity

  1st treatment cycle = 3 weeks

• 1-year survival rate (Phase 2)

  Survival time from date of tumor resection and device implantation

  12-months

• Relationship between overall survival and SSR3 (Phase 2)

  Survival time from date of tumor resection and device implantation

  through study completion, an average of 2 years

Secondary Outcomes (1)

• Incidence of side effects/toxicity associated with Sonication/ABX treatment

  12 months

Other Outcomes (3)

• Extent of tumor and peritumoral tissue covered by BBB opening

  1st cycle (cycle = 3 weeks)

• Objective response rate (RANO)

  6 months

• Measurement of circulating tumor DNA, methods and units for this measure are to be determined and still under evaluation.

  1st cycle, cycles 2 - 6 as applicable (cycle = 3 weeks)

Study Arms (1)

SC9/ABX (phase 1); SC9/ABX/Carboplatin (phase 2)

EXPERIMENTAL

Infusion of albumin-bound paclitaxel immediately followed by sonication using the SC9 device and microbubbles in order to open the blood-brain barrier in phase 1. In phase 2, patients will receive carboplatin immediately prior to sonication using the SC9 device and microbubbles in order to open the blood-brain barrier, then will receive albumin-bound paclitaxel upon completion of sonication.

Device: Sonication for opening of blood-brain barrier; Drug: Chemotherapy, albumin-bound paclitaxel; Drug: Chemotherapy, carboplatin

Interventions

Chemotherapy, carboplatin DRUG

Intravenous infusion of carboplatin over 30 minutes

Also known as: Paraplatin

SC9/ABX (phase 1); SC9/ABX/Carboplatin (phase 2)

Sonication for opening of blood-brain barrier DEVICE

Implantation of SC-9 device and repeat activation of 9 ultrasound emitters during i.v. injection of microbubbles

Also known as: SonoCloud-9 device, SC-9

SC9/ABX (phase 1); SC9/ABX/Carboplatin (phase 2)

Chemotherapy, albumin-bound paclitaxel DRUG

Intravenous infusion of ABX over 30 minutes

Also known as: Abraxane®, ABX

SC9/ABX (phase 1); SC9/ABX/Carboplatin (phase 2)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Confirmed diagnosis of Isocitrate Dehydrogenase 1 (IDH1) wild-type glioblastoma on pathology from initial surgery (e.g. IDH R132H neg); morphologic or molecular determination of grade 4
• Ability to undergo contrast-enhanced MRI
• Radiographic evidence of tumor recurrence/progression after failure of 1 - 2 lines of prior therapy
• Measurable or evaluable disease
• Measurable: contrast-enhancement (bidirectional diameters ≥ 1cm) on MRI
• Non-measurable/evaluable: contrast-enhancement diameters \< 1 cm
• Maximal tumor diameter pre-surgery ≤ 70 mm on T1wMRI
• Candidate for at least partial surgical resection
• Greater 12 weeks from completion of radiation therapy
• 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 (equivalent to Karnofsky Performance Status (KPS) of ≥70)
• Adequate hepatic, renal and bone marrow function, documented with normal laboratory values or no more than grade 1 outside the norm performed within 14 days prior to registration
• For patients with a childbearing potential
• Negative pregnancy test within 14 days prior to registration

You may not qualify if:

• Have multifocal disease that cannot be encompassed in the ultrasound fields:
• e.g. \> 70-mm apart
• tumor located in the posterior fossa
• Patients at risk of cranial wound dehiscence
• Have uncontrolled epilepsy or require treatment with enzyme-inducing antiepileptics
• Have clinical evidence of peripheral neuropathy on examination
• 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
• Medical contraindications to Abraxane® or carboplatin
• Have an uncontrolled intercurrent illness
• Are pregnant or nursing
• Have a history of active malignancy within 3 years prior to registration.
• Have a known history of hypersensitivity reactions to perflutren lipid microsphere components or to any of the inactive ingredients in Definity® (the FDA-approved ultrasound contrast agent to be used in this study)
• 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.

Sponsors & Collaborators

• Northwestern University: lead
• Bristol-Myers Squibb: collaborator
• CarThera: collaborator
• National Cancer Institute (NCI): collaborator

Study Sites (1)

Northwestern Memorial Hospital

Chicago, Illinois, 60611, United States

Location

Related Publications (6)

• Idbaih A, Canney M, Belin L, Desseaux C, Vignot A, Bouchoux G, Asquier N, Law-Ye B, Leclercq D, Bissery A, De Rycke Y, Trosch C, Capelle L, Sanson M, Hoang-Xuan K, Dehais C, Houillier C, Laigle-Donadey F, Mathon B, Andre A, Lafon C, Chapelon JY, Delattre JY, Carpentier A. Safety and Feasibility of Repeated and Transient Blood-Brain Barrier Disruption by Pulsed Ultrasound in Patients with Recurrent Glioblastoma. Clin Cancer Res. 2019 Jul 1;25(13):3793-3801. doi: 10.1158/1078-0432.CCR-18-3643. Epub 2019 Mar 19.

  PMID: 30890548 BACKGROUND

• Sonabend AM, Stupp R. Overcoming the Blood-Brain Barrier with an Implantable Ultrasound Device. Clin Cancer Res. 2019 Jul 1;25(13):3750-3752. doi: 10.1158/1078-0432.CCR-19-0932. Epub 2019 May 10.

  PMID: 31076548 BACKGROUND

• Zhang DY, Dmello C, Chen L, Arrieta VA, Gonzalez-Buendia E, Kane JR, Magnusson LP, Baran A, James CD, Horbinski C, Carpentier A, Desseaux C, Canney M, Muzzio M, Stupp R, Sonabend AM. Ultrasound-mediated Delivery of Paclitaxel for Glioma: A Comparative Study of Distribution, Toxicity, and Efficacy of Albumin-bound Versus Cremophor Formulations. Clin Cancer Res. 2020 Jan 15;26(2):477-486. doi: 10.1158/1078-0432.CCR-19-2182. Epub 2019 Dec 12.

  PMID: 31831565 BACKGROUND

• Gould A, Luan Y, Hou Y, Korobova FV, Chen L, Arrieta VA, Amidei C, Ward R, Gomez C, Castro B, Habashy K, Zhang D, Youngblood M, Dmello C, Bebawy J, Bouchoux G, Stupp R, Canney M, Yue F, Iruela-Arispe ML, Sonabend AM. Endothelial response to blood-brain barrier disruption in the human brain. JCI Insight. 2024 Dec 26;10(4):e187328. doi: 10.1172/jci.insight.187328.

  PMID: 39724015 DERIVED

• Sonabend AM, Gould A, Amidei C, Ward R, Schmidt KA, Zhang DY, Gomez C, Bebawy JF, Liu BP, Bouchoux G, Desseaux C, Helenowski IB, Lukas RV, Dixit K, Kumthekar P, Arrieta VA, Lesniak MS, Carpentier A, Zhang H, Muzzio M, Canney M, Stupp R. Repeated blood-brain barrier opening with an implantable ultrasound device for delivery of albumin-bound paclitaxel in patients with recurrent glioblastoma: a phase 1 trial. Lancet Oncol. 2023 May;24(5):509-522. doi: 10.1016/S1470-2045(23)00112-2.

  PMID: 37142373 DERIVED

• Dmello C, Sonabend A, Arrieta VA, Zhang DY, Kanojia D, Chen L, Gould A, Zhang J, Kang SJ, Winter J, Horbinski C, Amidei C, Gyorffy B, Cordero A, Chang CL, Castro B, Hsu P, Ahmed AU, Lesniak MS, Stupp R, Sonabend AM. Translocon-associated Protein Subunit SSR3 Determines and Predicts Susceptibility to Paclitaxel in Breast Cancer and Glioblastoma. Clin Cancer Res. 2022 Jul 15;28(14):3156-3169. doi: 10.1158/1078-0432.CCR-21-2563.

  PMID: 35552677 DERIVED

MeSH Terms

Conditions

Glioblastoma; Gliosarcoma

Interventions

Sonication; Drug Therapy; Albumin-Bound Paclitaxel; Carboplatin

Condition Hierarchy (Ancestors)

Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Investigative Techniques; Therapeutics; Paclitaxel; Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes; Albumins; Proteins; Amino Acids, Peptides, and Proteins; Coordination Complexes

Study Officials

• Roger Stupp, MD

  Northwestern University

  STUDY CHAIR

• Adam M Sonabend, MD

  Northwestern University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor, Feinberg School of Medicine, Neurological Surgery

Study Record Dates

• First Submitted: August 24, 2020
• First Posted: August 27, 2020
• Study Start: October 29, 2020
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2026
• Last Updated: April 13, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)