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

• ClinicalTrials.gov Identifier: NCT04528680
• Recruitment Status: Recruiting
• First Posted: August 27, 2020
• Last Update Posted: October 12, 2020
• Sponsor: Northwestern University
• Collaborators: CarThera; Bristol-Myers Squibb; Lantheus Medical Imaging
• Information provided by (Responsible Party): Adam Sonabend, Northwestern University

Tracking Information

• First Submitted Date: August 24, 2020
• First Posted Date: August 27, 2020
• Last Update Posted Date: October 12, 2020
• Estimated Study Start Date: October 2020
• Estimated Primary Completion Date: August 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 26, 2020)

• Dose limiting toxicity [ Time Frame: 1st treatment cycle = 3 weeks ]
  Occurrence of ≥ grade 3 treatment related toxicity
• 1-year survival rate [ Time Frame: 12-months ]
  Survival time from date of tumor resection and device implantation

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: August 26, 2020)

Incidence of side effects/toxicity associated with Sonication/ABX treatment [ Time Frame: 12 months ]

Safety and tolerance

• Original Secondary Outcome Measures: Same as current

Current Other Pre-specified Outcome Measures (submitted: October 8, 2020)

• Extent of tumor and peritumoral tissue covered by BBB opening [ Time Frame: 1st cycle (cycle = 3 weeks) ]
  increase in Gd contrast enhancement post sonication
• Objective response rate (RANO) [ Time Frame: 6 months ]
  measurement of tumor shrinkage (if there is residual disease)
• 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

Original Other Pre-specified Outcome Measures (submitted: August 26, 2020)

• Extent of tumor and peritumoral tissue covered by BBB opening [ Time Frame: 1st cycle (cycle = 3 weeks) ]
  increase in Gd contrast enhancement post sonication
• Objective response rate (RANO) [ Time Frame: 6 months ]
  measurement of tumor shrinkage (if there is residual disease)
• Measurement of circulation tumor DNA [ Time Frame: 1st cycle, cycles 2 - 6 as applicable (cycle = 3 weeks) ]
  compare before and after sonication

Descriptive Information

• Brief Title: Ultrasound-based Blood-brain Barrier Opening and Albumin-bound Paclitaxel for Recurrent Glioblastoma
• Official Title: Phase 1 / 2 Trial of Blood-brain Barrier Opening With an Implantable Ultrasound Device SonoCloud-9 and Treatment With Albumin-bound Paclitaxel in Patients With Recurrent Glioblastoma

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 this phase 1 trial increasing doses of chemotherapy will be delivered as long deemed safe and prior patient had not experienced severe toxicity. Once the the recommended dosing has been established, 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 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 will occur immediately after the test dose of chemotherapy is administered.

The objectives of this trial are to establish a safe and effective dose of ABX, 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.

• Detailed Description: Eligible patients will undergo craniotomy for tumor resection. During the tumor resection, an initial low dose of paclitaxel will be given following sonication. In select patients, the sonication procedure will occur immediately after the test dose of chemotherapy is administered.The sonication device will be implanted at the end of the procedure. 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 ABX starting dose is 40 mg/m2 of ABX, 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.
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

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

Intervention

• 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

Study Arms

Experimental: SC9/ABX

Infusion of albumin-bound paclitaxel immediately followed by sonication using the SC9 device and microbubbles in order to open the blood-brain barrier.

Interventions:

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

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, André 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.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: October 8, 2020): 39
• Original Estimated Enrollment (submitted: August 26, 2020): 37
• Estimated Study Completion Date: September 2025
• Estimated Primary Completion Date: August 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Confirmed diagnosis of Isocitrate Dehydrogenase 1 (IDH1) wild-type glioblastoma on pathology from initial surgery (e.g. IDH R132H neg)
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. Stable or decreasing dose of corticosteroids equivalent to ≤ 6 mg dexamethasone, for ≥ 7 days prior to registration
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 nab-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
7. Medical contraindications to Abraxane®
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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

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

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

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04528680
• Other Study ID Numbers: NU 20C03
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

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

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: Adam Sonabend, Northwestern University
• Study Sponsor: Northwestern University

Collaborators

• CarThera
• Bristol-Myers Squibb
• Lantheus Medical Imaging

Investigators

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

• PRS Account: Northwestern University
• Verification Date: October 2020