Blood-brain Barrier (BBB) Disruption Using Exablate Focused Ultrasound With Standard of Care Treatment of NSCLC Brain Mets

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Brain Tumor

Intervention / Treatment
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* Device: Blood Brain Barrier Disruption - Oncology
* Drug: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pembrolizumab with Exablate BBBD<br>Using Exablate Model 4000 Type 2 for the treatment of NSCLC brain metastases in subjects who are undergoing planned pembrolizumab monotherapy. | Device: Blood Brain Barrier Disruption - Oncology<br>* BBB opening via Exablate Type 2 system with microbubble resonators on the day of pembrolizumab infusion to treat brain metastases<br>* Other names: Exablate BBBD;Drug: Pembrolizumab<br>* Pembrolizumab infusion<br>|
| Active Comparator: Control Arm (Pembrolizumab only)<br>subjects will undergo planned pembrolizumab monotherapy. | Drug: Pembrolizumab<br>* Pembrolizumab infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | up to 6 months | 
| 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. | up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | up to 6 months | 
| 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. | up to 6 months | 
| 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. | up to 6 months |