Blood-brain Barrier (BBB) Disruption Using Exablate Focused Ultrasound With Standard of Care Treatment of NSCLC Brain Mets
Primary Purpose
Brain Tumor
Status
Recruiting
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Blood Brain Barrier Disruption - Oncology
Pembrolizumab
Sponsored by
About this trial
This is an interventional treatment trial for Brain Tumor
Eligibility Criteria
Inclusion Criteria:
- Participant is ≥ 18 years of age
- The participant provides written informed consent for the trial
- Participant is willing to comply with all study procedures for the duration of the study
- Subject has tumor biomarkers that are EGFR (epidermal growth factor receptor) and ALK (anaplastic lymphoma kinase) negative
- Participant is a NSCLC subject prescribed pembrolizumab monotherapy per standard of care
- Participant is diagnosed with at least 1 measurable brain metastasis ≥ 0.5 cm in longest diameter that is untreated, device-accessible and MR visible
- Participant has a Karnofsky Performance Status ≥ 70% and/or ECOG 0-2
- Female subject is confirmed NOT PREGNANT each procedure day. Male and Female subjects are utilizing highly effective contraception during the study and through 120 days (4 months) after the study
- Screening/Baseline laboratory values
Exclusion Criteria
- Subject is pregnant or breastfeeding,
- Participant has evidence of acute intracranial hemorrhage or significant calcifications in the focused ultrasound sonication beam path
- Participant at risk for spontaneous intracranial hemorrhage (e.g., history of metastatic melanoma or other tissue histology)
- Participant has signs and symptoms of increased intracranial pressure or symptomatic mass effect, midline shift or evidence of subfalcine, uncal or tonsillar herniation
- Participant receiving Bevacizumab (Avastin) therapy, or other drugs with a proclivity for causing bleeding
- History of bleeding disorder, coagulopathy or with a history of spontaneous brain tumor hemorrhage, anticoagulation or antiplatelet therapy or medication known to increase the risk of hemorrhage within washout period prior to treatment (i.e., antiplatelet or vitamin K inhibitor anticoagulants within 7 days, non-vitamin K inhibitor anticoagulants within 72 hours, or heparin-derived compounds within 48 hours of treatment)
- Participant has a known chronic viral infection such as Hepatitis B, Hepatitis C or HIV or has a known history of/active TB (Bacillus tuberculosis)
- Subjects with evidence of cranial or systemic infection
- Participant has received a solid organ or hematopoietic stem cell transplant
- Participant has received a live vaccine within 28 days prior to the first dose of study agent Examples of live vaccines include, but are not limited to measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), typhoid vaccine, and intranasal influenza vaccines (e.g., FluMist®)
- Participant has a severe or uncontrolled medical disorder that would, in the investigator's opinion, impair ability to receive study intervention
- Known sensitivity to DEFINITY® ultrasound contrast agent or hypersensitivity to perflutren microsphere or its components, e.g., polyethylene glycol, as found in MiraLAX and bowel prep products
- Contraindications to MRI and gadolinium-DTPA including non-MRI-compatible implanted devices, severe claustrophobia, unable to lie supine in MRI
- Severely impaired renal function with estimated glomerular filtration rate <30 mL/min/1.73m2, creatinine >1.5 ULN and/or on dialysis
- Subjects with significant liver dysfunction, e.g., history of cirrhosis (hemochromatosis or severe alcohol abuse), or active hepatitis (autoimmune or infectious) with elevated AST, ALT INR or bilirubin (ALT: Male 21-72 units/L; Female 9-52 units/L; AST: Male 17-59 units/L, Female 14-36 units/L; INR >1.3; bilirubin >5 times lab normal)
- Subject is currently enrolled in another intervention based clinical trial
- Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug
- Has a known additional malignancy that is progressing or has required active treatment within the past 3 years
- Presence of leptomeningeal disease
- Contraindications to pembrolizumab or has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients
- Has a diagnosis of active autoimmune disease (e.g., autoimmune Hepatitis, Guillain-Barre Syndrome, etc.) requiring systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. History of (non-infectious) pneumonitis that requires steroids or has current pneumonitis
- Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
- Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
Sites / Locations
- St. Joseph's Hospital and Medical CenterRecruiting
- Miami Cancer Institute at Baptist HealthRecruiting
- University of MarylandRecruiting
- Johnston Willis HospitalRecruiting
- Sunnybrook Research InstituteRecruiting
- Seoul National University Hospital
- Samsung Medical Center
- Severance Hospital, Yonsei University Health System
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Active Comparator
Arm Label
Pembrolizumab with Exablate BBBD
Control Arm (Pembrolizumab only)
Arm Description
Using Exablate Model 4000 Type 2 for the treatment of NSCLC brain metastases in subjects who are undergoing planned pembrolizumab monotherapy.
subjects will undergo planned pembrolizumab monotherapy.
Outcomes
Primary Outcome Measures
Adverse events
Adverse events [ Time Frame: Through study completion, up to 6 months]. All adverse events and/or Serious Adverse Events will be documented and reported according to CTCAE criteria.
tumor lesion(s) on the MRI images
Efficacy will be determined by the response of the tumor lesion(s) compared to baseline. Tumor lesions on the MRI images (units: mm) will be measured every three weeks up to six months.
Secondary Outcome Measures
evaluation of Neuro Oncology Brain Mets (RANO-BM) response
The evaluation of the percentages of subjects that achieved the stable disease (SD), partial response (PR) as the best objective response using the response assessment in Neuro Oncology Brain Mets (RANO-BM) response criteria measured at baseline and every 3 weeks during each treatment cycle to up to 6 months of therapy.
Time to response for brain metastases by treatment arm
The time to achieve a confirmed complete response or partial response for brain metastases by treatment arm as assessed using the RANO-BM criteria evaluated every 3 weeks up to 6 months during treatment cycles.
time to response for brain mets by treatment arm
The time to achieve a confirmed complete response or partial response for brain metastases by treatment arm as assessed using the RANO-BM criteria evaluated every 3 weeks up to 6 months during treatment cycles.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT05317858
Brief Title
Blood-brain Barrier (BBB) Disruption Using Exablate Focused Ultrasound With Standard of Care Treatment of NSCLC Brain Mets
Official Title
A Randomized Pivotal Study Assessing the Efficacy of Targeted Blood-brain Barrier (BBB) Disruption Using Exablate Focused Ultrasound During the Standard of Care Treatment of Brain Metastases of Non-small Cell Lung Cancer (NSCLC) Origin
Study Type
Interventional
2. Study Status
Record Verification Date
October 2023
Overall Recruitment Status
Recruiting
Study Start Date
August 12, 2022 (Actual)
Primary Completion Date
June 1, 2024 (Anticipated)
Study Completion Date
December 1, 2024 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
InSightec
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
Yes
Device Product Not Approved or Cleared by U.S. FDA
Yes
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
The purpose of this study is to evaluate the safety and efficacy of targeted blood brain barrier disruption with Exablate Model 4000 Type 2.0/2.1 for the treatment of NSCLC brain metastases in patients who are undergoing planned pembrolizumab monotherapy.
Detailed Description
This is a prospective, multi-center, randomized, two-arm, controlled, pivotal clinical trial to evaluate the safety and efficacy of targeted blood brain barrier disruption using Exablate Model 4000 Type 2 for the treatment of NSCLC brain metastases in subjects who are undergoing planned pembrolizumab monotherapy for their primary disease. The study will be conducted at up to 20 centers in the US. The immunotherapy regimen (every 3 weeks for 6 cycles) of pembrolizumab is per the FDA approved labeling for pembrolizumab (Keytruda®) and the subjects prescribed standard of care therapy for their primary NSCLC. The study aims to demonstrate superiority of Exablate BBBD targeted to their brain metastases over the standard of care without Exablate BBBD with respect to the percentage of subjects achieving Objective Response Rate (ORR) by 6 months follow-up.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Brain Tumor
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
20 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Pembrolizumab with Exablate BBBD
Arm Type
Experimental
Arm Description
Using Exablate Model 4000 Type 2 for the treatment of NSCLC brain metastases in subjects who are undergoing planned pembrolizumab monotherapy.
Arm Title
Control Arm (Pembrolizumab only)
Arm Type
Active Comparator
Arm Description
subjects will undergo planned pembrolizumab monotherapy.
Intervention Type
Device
Intervention Name(s)
Blood Brain Barrier Disruption - Oncology
Other Intervention Name(s)
Exablate BBBD
Intervention Description
BBB opening via Exablate Type 2 system with microbubble resonators on the day of pembrolizumab infusion to treat brain metastases
Intervention Type
Drug
Intervention Name(s)
Pembrolizumab
Intervention Description
Pembrolizumab infusion
Primary Outcome Measure Information:
Title
Adverse events
Description
Adverse events [ Time Frame: Through study completion, up to 6 months]. All adverse events and/or Serious Adverse Events will be documented and reported according to CTCAE criteria.
Time Frame
up to 6 months
Title
tumor lesion(s) on the MRI images
Description
Efficacy will be determined by the response of the tumor lesion(s) compared to baseline. Tumor lesions on the MRI images (units: mm) will be measured every three weeks up to six months.
Time Frame
up to 6 months
Secondary Outcome Measure Information:
Title
evaluation of Neuro Oncology Brain Mets (RANO-BM) response
Description
The evaluation of the percentages of subjects that achieved the stable disease (SD), partial response (PR) as the best objective response using the response assessment in Neuro Oncology Brain Mets (RANO-BM) response criteria measured at baseline and every 3 weeks during each treatment cycle to up to 6 months of therapy.
Time Frame
up to 6 months
Title
Time to response for brain metastases by treatment arm
Description
The time to achieve a confirmed complete response or partial response for brain metastases by treatment arm as assessed using the RANO-BM criteria evaluated every 3 weeks up to 6 months during treatment cycles.
Time Frame
up to 6 months
Title
time to response for brain mets by treatment arm
Description
The time to achieve a confirmed complete response or partial response for brain metastases by treatment arm as assessed using the RANO-BM criteria evaluated every 3 weeks up to 6 months during treatment cycles.
Time Frame
up to 6 months
Other Pre-specified Outcome Measures:
Title
Patient reported quality of life measurement questionnaires
Description
patient reported health and quality of life questionnaire completed every 3 weeks up to 6 months during treatment cycle.
Time Frame
up to 6 months
Title
Measurement of BBBD disruption
Description
Measurement of blood brain barrier disruption (BBBD) assessment of post-sonication contrast-enhanced MR imaging evaluated every 3 weeks up to 6 months in comparison with pre-sonication imaging.
Time Frame
up to 6 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
100 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Participant is ≥ 18 years of age
The participant provides written informed consent for the trial
Participant is willing to comply with all study procedures for the duration of the study
Subject has tumor biomarkers that are EGFR (epidermal growth factor receptor) and ALK (anaplastic lymphoma kinase) negative
Participant is a NSCLC subject prescribed pembrolizumab monotherapy per standard of care
Participant is diagnosed with at least 1 measurable brain metastasis ≥ 0.5 cm in longest diameter that is untreated, device-accessible and MR visible
Participant has a Karnofsky Performance Status ≥ 70% and/or ECOG 0-2
Female subject is confirmed NOT PREGNANT each procedure day. Male and Female subjects are utilizing highly effective contraception during the study and through 120 days (4 months) after the study
Screening/Baseline laboratory values
Exclusion Criteria
Subject is pregnant or breastfeeding,
Participant has evidence of acute intracranial hemorrhage or significant calcifications in the focused ultrasound sonication beam path
Participant at risk for spontaneous intracranial hemorrhage (e.g., history of metastatic melanoma or other tissue histology)
Participant has signs and symptoms of increased intracranial pressure or symptomatic mass effect, midline shift or evidence of subfalcine, uncal or tonsillar herniation
Participant receiving Bevacizumab (Avastin) therapy, or other drugs with a proclivity for causing bleeding
History of bleeding disorder, coagulopathy or with a history of spontaneous brain tumor hemorrhage, anticoagulation or antiplatelet therapy or medication known to increase the risk of hemorrhage within washout period prior to treatment (i.e., antiplatelet or vitamin K inhibitor anticoagulants within 7 days, non-vitamin K inhibitor anticoagulants within 72 hours, or heparin-derived compounds within 48 hours of treatment)
Participant has a known chronic viral infection such as Hepatitis B, Hepatitis C or HIV or has a known history of/active TB (Bacillus tuberculosis)
Subjects with evidence of cranial or systemic infection
Participant has received a solid organ or hematopoietic stem cell transplant
Participant has received a live vaccine within 28 days prior to the first dose of study agent Examples of live vaccines include, but are not limited to measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), typhoid vaccine, and intranasal influenza vaccines (e.g., FluMist®)
Participant has a severe or uncontrolled medical disorder that would, in the investigator's opinion, impair ability to receive study intervention
Known sensitivity to DEFINITY® ultrasound contrast agent or hypersensitivity to perflutren microsphere or its components, e.g., polyethylene glycol, as found in MiraLAX and bowel prep products
Contraindications to MRI and gadolinium-DTPA including non-MRI-compatible implanted devices, severe claustrophobia, unable to lie supine in MRI
Severely impaired renal function with estimated glomerular filtration rate <30 mL/min/1.73m2, creatinine >1.5 ULN and/or on dialysis
Subjects with significant liver dysfunction, e.g., history of cirrhosis (hemochromatosis or severe alcohol abuse), or active hepatitis (autoimmune or infectious) with elevated AST, ALT INR or bilirubin (ALT: Male 21-72 units/L; Female 9-52 units/L; AST: Male 17-59 units/L, Female 14-36 units/L; INR >1.3; bilirubin >5 times lab normal)
Subject is currently enrolled in another intervention based clinical trial
Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug
Has a known additional malignancy that is progressing or has required active treatment within the past 3 years
Presence of leptomeningeal disease
Contraindications to pembrolizumab or has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients
Has a diagnosis of active autoimmune disease (e.g., autoimmune Hepatitis, Guillain-Barre Syndrome, etc.) requiring systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. History of (non-infectious) pneumonitis that requires steroids or has current pneumonitis
Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Nadir Alikacem
Phone
+12146302000
Email
nadira@insightec.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Manmeet Ahluwalia, MD, MBA
Organizational Affiliation
Miami Cancer Institute, Baptist Health South Florida
Official's Role
Principal Investigator
Facility Information:
Facility Name
St. Joseph's Hospital and Medical Center
City
Phoenix
State/Province
Arizona
ZIP/Postal Code
85013
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Phase O Navigator
Phone
602-406-8605
Email
research@ivybraintumorcenter.org
First Name & Middle Initial & Last Name & Degree
Nader Sanai, MD
Facility Name
Miami Cancer Institute at Baptist Health
City
Miami
State/Province
Florida
ZIP/Postal Code
33176
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Daylan L Santana, RN
Phone
786-527-8528
Email
DaylenS@baptisthealth.net
First Name & Middle Initial & Last Name & Degree
Juliana Montoya
Phone
786-527-8864
Email
Juliana.Montoya@BaptistHealth.ne
First Name & Middle Initial & Last Name & Degree
Manmeet S Ahluwalia, MD
Facility Name
University of Maryland
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21201
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Kaitlyn Henry
Phone
410-328-0939
Email
KHenry@som.umaryland.edu
First Name & Middle Initial & Last Name & Degree
Charlie Klontz
Phone
410-328-5332
Email
CMKlontz@som.umaryland.edu
First Name & Middle Initial & Last Name & Degree
Graeme Woodworth, MD
First Name & Middle Initial & Last Name & Degree
Howard Eisenberg, MD
First Name & Middle Initial & Last Name & Degree
Alexander Ksendzovsky, MD
Facility Name
Johnston Willis Hospital
City
Richmond
State/Province
Virginia
ZIP/Postal Code
23235
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Kanwalcharan S Sahni, MD
Phone
804-330-4990
Email
ksinghsahni@gmail.com
Facility Name
Sunnybrook Research Institute
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M4N 3M5
Country
Canada
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Meheleth Llinas
Phone
416-480-6100
Ext
2476
Email
maheleth.llinas@sunnybrook.ca
First Name & Middle Initial & Last Name & Degree
Nir Lipsman, MD
Facility Name
Seoul National University Hospital
City
Seoul
ZIP/Postal Code
03080
Country
Korea, Republic of
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Eun J Lee, MD
Phone
+82-10-4110-0121
Email
eunjlee21@snu.ac.kr
Facility Name
Samsung Medical Center
City
Seoul
ZIP/Postal Code
06351
Country
Korea, Republic of
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jung-il Lee, MD
Phone
+82-2-3410-3494
Email
jilee.lee@samsung.com
Facility Name
Severance Hospital, Yonsei University Health System
City
Soeul
ZIP/Postal Code
03722
Country
Korea, Republic of
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Eunjung Kweon
Phone
82-10-2866-1044
Email
kweonej@yuhs.ac
First Name & Middle Initial & Last Name & Degree
Hyun H Jung, MD
12. IPD Sharing Statement
Learn more about this trial
Blood-brain Barrier (BBB) Disruption Using Exablate Focused Ultrasound With Standard of Care Treatment of NSCLC Brain Mets
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