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

Primary Purpose

Glioblastoma, Gliosarcoma, GBM

Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Sonication for opening of blood-brain barrier
Chemotherapy, albumin-bound paclitaxel
Chemotherapy, carboplatin
Sponsored by
Northwestern University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Glioblastoma focused on measuring ultrasound, SonoCloud, blood-brain barrier, paclitaxel, albumin-bound paclitaxel, Abraxane®, carboplatin

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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)

Sites / Locations

  • Northwestern Memorial HospitalRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

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

Arm Description

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.

Outcomes

Primary Outcome Measures

Dose limiting toxicity (Phase1)
Occurrence of ≥ grade 3 treatment related toxicity
1-year survival rate (Phase 2)
Survival time from date of tumor resection and device implantation
Relationship between overall survival and SSR3 (Phase 2)
Survival time from date of tumor resection and device implantation

Secondary Outcome Measures

Incidence of side effects/toxicity associated with Sonication/ABX treatment
Safety and tolerance

Full Information

First Posted
August 24, 2020
Last Updated
May 24, 2023
Sponsor
Northwestern University
Collaborators
CarThera, Bristol-Myers Squibb, Lantheus Medical Imaging
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1. Study Identification

Unique Protocol Identification Number
NCT04528680
Brief Title
Ultrasound-based Blood-brain Barrier Opening and Albumin-bound Paclitaxel and Carboplatin for Recurrent Glioblastoma
Acronym
SC9/ABX
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
Study Type
Interventional

2. Study Status

Record Verification Date
May 2023
Overall Recruitment Status
Recruiting
Study Start Date
October 29, 2020 (Actual)
Primary Completion Date
September 10, 2024 (Anticipated)
Study Completion Date
September 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Northwestern University
Collaborators
CarThera, Bristol-Myers Squibb, Lantheus Medical Imaging

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
Yes
Data Monitoring Committee
Yes

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Glioblastoma, Gliosarcoma, GBM, Glioblastoma Multiforme, Glioblastoma, IDH-wildtype, Recurrent Glioblastoma
Keywords
ultrasound, SonoCloud, blood-brain barrier, paclitaxel, albumin-bound paclitaxel, Abraxane®, carboplatin

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
57 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
SC9/ABX (phase 1); SC9/ABX/Carboplatin (phase 2)
Arm Type
Experimental
Arm Description
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.
Intervention Type
Device
Intervention Name(s)
Sonication for opening of blood-brain barrier
Other Intervention Name(s)
SonoCloud-9 device, SC-9
Intervention Description
Implantation of SC-9 device and repeat activation of 9 ultrasound emitters during i.v. injection of microbubbles
Intervention Type
Drug
Intervention Name(s)
Chemotherapy, albumin-bound paclitaxel
Other Intervention Name(s)
Abraxane®, ABX
Intervention Description
Intravenous infusion of ABX over 30 minutes
Intervention Type
Drug
Intervention Name(s)
Chemotherapy, carboplatin
Other Intervention Name(s)
Paraplatin
Intervention Description
Intravenous infusion of carboplatin over 30 minutes
Primary Outcome Measure Information:
Title
Dose limiting toxicity (Phase1)
Description
Occurrence of ≥ grade 3 treatment related toxicity
Time Frame
1st treatment cycle = 3 weeks
Title
1-year survival rate (Phase 2)
Description
Survival time from date of tumor resection and device implantation
Time Frame
12-months
Title
Relationship between overall survival and SSR3 (Phase 2)
Description
Survival time from date of tumor resection and device implantation
Time Frame
through study completion, an average of 2 years
Secondary Outcome Measure Information:
Title
Incidence of side effects/toxicity associated with Sonication/ABX treatment
Description
Safety and tolerance
Time Frame
12 months
Other Pre-specified Outcome Measures:
Title
Extent of tumor and peritumoral tissue covered by BBB opening
Description
increase in Gd contrast enhancement post sonication
Time Frame
1st cycle (cycle = 3 weeks)
Title
Objective response rate (RANO)
Description
measurement of tumor shrinkage (if there is residual disease)
Time Frame
6 months
Title
Measurement of circulating tumor DNA, methods and units for this measure are to be determined and still under evaluation.
Description
compare before and after sonication
Time Frame
1st cycle, cycles 2 - 6 as applicable (cycle = 3 weeks)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: 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 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. Have the ability to understand and the willingness to sign a written informed consent prior to registration on study Be willing and able to comply with the protocol for the duration of the study 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: 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. 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 (due to device)
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Christina Amidei, APN, PhD
Phone
(312) 695-9124
Email
christina.amidei@nm.org
First Name & Middle Initial & Last Name or Official Title & Degree
Roger Stupp, MD
Email
roger.stupp@northwestern.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Roger Stupp, MD
Organizational Affiliation
Northwestern University
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Adam M Sonabend, MD
Organizational Affiliation
Northwestern University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Northwestern Memorial Hospital
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Christina Amidei, PhD, APN
Phone
312-695-9124
Email
christina.amidei@nm.org
First Name & Middle Initial & Last Name & Degree
Adam M Sonabend, MD
First Name & Middle Initial & Last Name & Degree
Roger Stupp, MD
First Name & Middle Initial & Last Name & Degree
Karan Dixit, MD
First Name & Middle Initial & Last Name & Degree
Priya Kumthekar, MD
First Name & Middle Initial & Last Name & Degree
Rimas V Lukas, MD

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
30890548
Citation
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.
Results Reference
background
PubMed Identifier
31076548
Citation
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.
Results Reference
background
PubMed Identifier
31831565
Citation
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.
Results Reference
background
PubMed Identifier
35552677
Citation
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.
Results Reference
derived

Learn more about this trial

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

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