Ultrasound-based Blood-brain Barrier Opening and Albumin-bound Paclitaxel and Carboplatin for Recurrent Glioblastoma (SC9/ABX)

• ClinicalTrials.gov Identifier: NCT04528680
• Recruitment Status: Recruiting
• First Posted: August 27, 2020
• Last Update Posted: May 26, 2023
• Sponsor: Northwestern University
• Collaborators: CarThera; Bristol-Myers Squibb; Lantheus Medical Imaging
• Information provided by (Responsible Party): Adam M Sonabend, Northwestern University

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Glioblastoma; Gliosarcoma; GBM; Glioblastoma Multiforme; Glioblastoma, IDH-wildtype; Recurrent Glioblastoma	Device: Sonication for opening of blood-brain barrier; Drug: Chemotherapy, albumin-bound paclitaxel; Drug: Chemotherapy, carboplatin	Phase 1; Phase 2

Detailed Description:

Eligible patients will undergo craniotomy for tumor resection. During the tumor resection and when possible, an initial low dose of albumin-bound paclitaxel will be given following sonication. In select patients, the sonication procedure may occur immediately after the test dose of chemotherapy is administered. The sonication device will be implanted at the end of the procedure. In phase 1, about two weeks after surgery, patients will undergo sonication and albumin-bound paclitaxel administration with MRI to quantify extent of blood brain barrier opening. Sonication and administration of albumin-bound paclitaxel will continue every 3 weeks until disease progression. The planned albumin-bound paclitaxel starting dose is 40 mg/m2, to be escalated in the absence of significant toxicity up to 260 mg/m2. Blood samples for circulating tumor DNA will also be collected before and after each sonication. In phase 2, pre-sonication carboplatin at AUC 5 will be added to the regimen, with a safety run-in for the first 6 patients.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 57 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase 1 / 2 Trial of Blood-brain Barrier Opening With an Implantable Ultrasound Device SonoCloud-9 and Treatment With Albumin-bound Paclitaxel and Carboplatin in Patients With Recurrent Glioblastoma
• Actual Study Start Date: October 29, 2020
• Estimated Primary Completion Date: September 10, 2024
• Estimated Study Completion Date: September 2025

Arms and Interventions

Arm

Intervention/treatment

Experimental: SC9/ABX (phase 1); SC9/ABX/Carboplatin (phase 2); 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; Implantation of SC-9 device and repeat activation of 9 ultrasound emitters during i.v. injection of microbubbles; Other Name: SonoCloud-9 device, SC-9; Drug: Chemotherapy, albumin-bound paclitaxel; Intravenous infusion of ABX over 30 minutes; Other Names: Abraxane®; ABX; Drug: Chemotherapy, carboplatin; Intravenous infusion of carboplatin over 30 minutes; Other Name: Paraplatin

Outcome Measures

Primary Outcome Measures :

1. Dose limiting toxicity (Phase1) [ Time Frame: 1st treatment cycle = 3 weeks ]
   Occurrence of ≥ grade 3 treatment related toxicity
2. 1-year survival rate (Phase 2) [ Time Frame: 12-months ]
   Survival time from date of tumor resection and device implantation
3. Relationship between overall survival and SSR3 (Phase 2) [ Time Frame: through study completion, an average of 2 years ]
   Survival time from date of tumor resection and device implantation

Secondary Outcome Measures :

1. Incidence of side effects/toxicity associated with Sonication/ABX treatment [ Time Frame: 12 months ]
   Safety and tolerance

Other Outcome Measures:

1. Extent of tumor and peritumoral tissue covered by BBB opening [ Time Frame: 1st cycle (cycle = 3 weeks) ]
   increase in Gd contrast enhancement post sonication
2. Objective response rate (RANO) [ Time Frame: 6 months ]
   measurement of tumor shrinkage (if there is residual disease)
3. Measurement of circulating tumor DNA, methods and units for this measure are to be determined and still under evaluation. [ Time Frame: 1st cycle, cycles 2 - 6 as applicable (cycle = 3 weeks) ]
   compare before and after sonication

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. 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
2. Ability to undergo contrast-enhanced MRI
3. Radiographic evidence of tumor recurrence/progression after failure of 1 - 2 lines of prior therapy

4. Measurable or evaluable disease

   1. Measurable: contrast-enhancement (bidirectional diameters ≥ 1cm) on MRI
   2. Non-measurable/evaluable: contrast-enhancement diameters < 1 cm
5. Maximal tumor diameter pre-surgery ≤ 70 mm on T1wMRI
6. Candidate for at least partial surgical resection
7. Greater 12 weeks from completion of radiation therapy
8. Age ≥ 18 years
9. 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.
10. WHO performance status ≤ 2 (equivalent to Karnofsky Performance Status (KPS) of ≥70)
11. 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

12. For patients with a childbearing potential

    1. Negative pregnancy test within 14 days prior to registration
    2. Agreement to use adequate contraception for the duration of study participation, and for 3 and 6 months after the last dose of albumin-bound paclitaxel for men and women of childbearing potential, respectively.
13. Have the ability to understand and the willingness to sign a written informed consent prior to registration on study
14. Be willing and able to comply with the protocol for the duration of the study
15. Provide written, signed and dated informed consent prior to study registration. NOTE: no study-specific screening procedures may be performed until written consent has been obtained

Exclusion Criteria:

1. Have multifocal disease that cannot be encompassed in the ultrasound fields:

   1. e.g. > 70-mm apart
   2. tumor located in the posterior fossa
2. Patients at risk of cranial wound dehiscence
3. Have uncontrolled epilepsy or require treatment with enzyme-inducing antiepileptics
4. Have clinical evidence of peripheral neuropathy on examination
5. Have received any other investigational agents within 4 weeks of registration
6. Have received prior therapy with or have history of allergic reactions attributed to compounds of similar chemical or biologic composition to paclitaxel or carboplatin
7. Medical contraindications to Abraxane® or carboplatin
8. Have an uncontrolled intercurrent illness
9. Are pregnant or nursing
10. Have a history of active malignancy within 3 years prior to registration.
11. 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)
12. Patients with coils, clips, shunts, intravascular stents, and/or non-removable wafer, non resorbable dura substitute, or reservoirs.
13. Patients with medical need to continue antiplatelet therapy.
14. 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).
15. Patients with impaired thermo-regulation or temperature sensation (due to device)

Contacts and Locations

Contacts

Contact: Christina Amidei, APN, PhD; (312) 695-9124; christina.amidei@nm.org

Contact: Roger Stupp, MD; roger.stupp@northwestern.edu

Locations

United States, Illinois

Northwestern Memorial Hospital; Recruiting

Chicago, Illinois, United States, 60611

Contact: Christina Amidei, PhD, APN 312-695-9124 christina.amidei@nm.org

Principal Investigator: Adam M Sonabend, MD

Principal Investigator: Roger Stupp, MD

Sub-Investigator: Karan Dixit, MD

Sub-Investigator: Priya Kumthekar, MD

Sub-Investigator: Rimas V Lukas, MD

Sponsors and Collaborators

Northwestern University

CarThera

Bristol-Myers Squibb

Lantheus Medical Imaging

Investigators

• Study Chair: Roger Stupp, MD; Northwestern University
• Principal Investigator: Adam M Sonabend, MD; Northwestern University

More Information

Publications:

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.

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.

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Adam M Sonabend, Assistant Professor, Feinberg School of Medicine, Neurological Surgery, Northwestern University
• ClinicalTrials.gov Identifier: NCT04528680
• Other Study ID Numbers: NU 20C03
• First Posted: August 27, 2020
• Last Update Posted: May 26, 2023
• Last Verified: May 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: Yes

Keywords provided by Adam M Sonabend, Northwestern University:

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

Additional relevant MeSH terms:

Glioblastoma; Gliosarcoma; Recurrence; Disease Attributes; Pathologic Processes; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Paclitaxel; Carboplatin; Albumin-Bound Paclitaxel; Antineoplastic Agents, Phytogenic; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Molecular Mechanisms of Pharmacological Action