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

August 17, 2026 updated by: InSightec

A Randomized Pivotal Study Assessing the Safety and Efficacy of Targeted Blood-brain Barrier (BBB) Opening Using Exablate Focused Ultrasound During the Standard of Care Treatment of Brain Metastases of Non-small Cell Lung Cancer (NSCLC) Origin

The purpose of this study is to evaluate the safety and efficacy of targeted blood brain barrier opening with Exablate Model 4000 Type 2.0/2.1 for the treatment of NSCLC brain metastases in patients who are undergoing planned FDA approved, on-label systemic therapy utilizing immune checkpoint inhibitors.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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 opening using Exablate Model 4000 Type 2 for the treatment of NSCLC brain metastases in subjects who are undergoing planned FDA approved, on-label systemic therapy utilizing immune checkpoint inhibitors for their primary disease. The study will be conducted at up to 30 centers in the US. The immunotherapy regimen (every 3 weeks for 6 cycles) of prescribed ICI therapy is per the FDA approved labeling and the subjects prescribed standard of care therapy for their primary NSCLC. The study aims to demonstrate superiority of Exablate BBBO targeted to their brain metastases over the standard of care without Exablate BBBO with respect to the percentage of subjects achieving Objective Response Rate (ORR) by 6 months follow-up.

Study Type

Interventional

Enrollment (Estimated)

30

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • Canada
    • Ontario
      • Toronto, Ontario, Canada, M4N 3M5
        • Active, not recruiting
        • Sunnybrook Research Institute
  • South Korea
      • Seoul, South Korea
        • Not yet recruiting
        • Seoul National University Hospital
        • Contact:
        • Principal Investigator:
          • Eun-jung Lee
      • Soeul, South Korea
        • Not yet recruiting
        • Severance Hospital, Yonsei University Health System
        • Contact:
        • Principal Investigator:
          • Hyun Ho Jung
    • Seoul
      • Seoul, Seoul, South Korea, 06351
        • Not yet recruiting
        • Samsung Medical Center
        • Contact:
        • Principal Investigator:
          • Kyung-won Chang
  • United States
    • Arizona
      • Phoenix, Arizona, United States, 85013
        • Withdrawn
        • St. Joseph's Hospital and Medical Center
    • California
      • Newport Beach, California, United States, 92663
        • Recruiting
        • Hoag Memorial Hospital Presbyterian
        • Contact:
        • Contact:
    • Florida
      • Fort Lauderdale, Florida, United States, 33316
        • Recruiting
        • Broward Health
        • Contact:
        • Contact:
        • Principal Investigator:
          • Shaye Moskowitz, MD
        • Sub-Investigator:
          • Mehmet Hepgur, MD
      • Miami, Florida, United States, 33176
        • Recruiting
        • Miami Cancer Institute at Baptist Health
        • Principal Investigator:
          • Manmeet S Ahluwalia, MD
        • Contact:
      • Tampa, Florida, United States, 33612
        • Recruiting
        • Moffitt Cancer Center
        • Contact:
        • Principal Investigator:
          • Yolanda Pina, Neuro-Oncology
    • Maryland
      • Baltimore, Maryland, United States, 21201
        • Recruiting
        • University of Maryland
        • Principal Investigator:
          • Graeme Woodworth, MD
        • Sub-Investigator:
          • Howard Eisenberg, MD
        • Sub-Investigator:
          • Alexander Ksendzovsky, MD
        • Contact:
        • Contact:
    • North Carolina
      • Winston-Salem, North Carolina, United States, 27103
        • Recruiting
        • Atrium Health Wake Forest Baptist
        • Contact:
        • Contact:
        • Principal Investigator:
          • Adrian Laxton, BA, MA, MD, FRCSC, FAANS
    • Oregon
      • Portland, Oregon, United States, 97239
        • Recruiting
        • Oregon Health & Science University
        • Contact:
        • Principal Investigator:
          • Ahmed Raslan, MBBCh, MSc, MD, FAANS
    • Rhode Island
      • Providence, Rhode Island, United States, 02903
    • Virginia
      • Richmond, Virginia, United States, 23235
        • Active, not recruiting
        • Johnston Willis Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 100 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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
  • Participant has a Karnofsky Performance Status ≥ 70% and/or ECOG 0-2
  • Participant is a NSCLC subject prescribed immune checkpoint inhibitor systemic therapy according to on-label use with the target brain lesion(s) measuring ≥ 0.5 cm in longest diameter. Target mets may include: De novo mets for which surgery and radiation can be deferred, Mets with or without history of prior radiation, Mets with history of radiation after at least 8 weeks since last radiation treatment, and In the event a previously treated met has progressed according to institutional practice within 4 weeks post radiation treatment, the met may be study eligible, and/or if in the opinion of the Investigator, the subject may benefit from the study procedure.
  • Female subject is not planning pregnancy during the study duration and confirmed NOT PREGNANT each procedure day.
  • Screening/Baseline laboratory values Screening/Baseline should adhere to local standard of care lab values for ICI therapy

Exclusion Criteria

  • Participant has evidence of acute intracranial hemorrhage
  • 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 disorders or tissue pathologies which increase the subject's risk of hemorrhage for anticoagulation medications, implement pre-surgical standard procedure to avoid increased risk of a bleeding event.
  • Participant has an infectious viral infection such as active Hepatitis B, Hepatitis C or detectable HIV viral load or participants with active bacterial infection such as TB (Bacillus tuberculosis) that may, in the opinion of the investigator, interfere with the subject receiving the study therapy or procedures or otherwise impact their participation in the trial.
  • 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 on-study ICI infusion with or without Exablate.
  • 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.
  • Subjects with significant liver dysfunction, (cirrhosis, hemochromatosis, severe alcohol abuse, or active hepatitis (autoimmune or infectious))
  • 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 on-study ICI infusion with or without Exablate. Note: prophylactic steroid use for ICI and chemotherapy infusion per institutional practice is allowed per protocol.
  • Has a known additional malignancy that requires active treatment that would interfere with study procedures.
  • Known presence of leptomeningeal disease.
  • 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.
  • Subject is currently enrolled in another intervention based clinical trial

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: ICI Systemic Therapy with Exablate BBBO
Using Exablate Model 4000 Type 2 for the treatment of NSCLC brain metastases in subjects who are undergoing planned ICI Systemic Therapy.
Drug: Pembrolizumab
Pembrolizumab infusion
Other Names:
  • KEYTRUDA
Drug: Nivolumab
Nivolumab infusion
Device: Blood Brain Barrier Opening - Oncology
BBB opening via Exablate Type 2 system with microbubble resonators on the day of ICI infusion to treat brain metastases.
Other Names:
  • Exablate BBBO
Drug: Atezolizumab
Atezolizumab infusion
Other Names:
  • Tecentriq
Drug: Cemiplimab
Cemiplimab infusion
Other Names:
  • LIBTAYO
Drug: Iptilimumab
Iptilimumab infusion
Active Comparator: Control Arm (ICI Systemic Therapy on-label use only)
subjects will undergo planned on-label ICI Systemic Therapy.
Drug: Pembrolizumab
Pembrolizumab infusion
Other Names:
  • KEYTRUDA
Drug: Nivolumab
Nivolumab infusion
Drug: Atezolizumab
Atezolizumab infusion
Other Names:
  • Tecentriq
Drug: Cemiplimab
Cemiplimab infusion
Other Names:
  • LIBTAYO
Drug: Iptilimumab
Iptilimumab infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Adverse events
Time Frame: up to 6 months
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
Time Frame: up to 6 months
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
Time Frame: up to 6 months
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 [applicable to the completed stage 1a only]
Time Frame: up to 6 months
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

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Patient reported quality of life measurement questionnaires
Time Frame: up to 6 months
patient reported health and quality of life questionnaire completed every 3 weeks up to 6 months during treatment cycle.
up to 6 months
Measurement of BBB Opening
Time Frame: up to 6 months
Measurement of blood brain barrier opening (BBBO) assessment of post-sonication contrast-enhanced MR imaging evaluated every 3 weeks up to 6 months in comparison with pre-sonication imaging.
up to 6 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

InSightec

Investigators

  • Principal Investigator: Manmeet Ahluwalia, MD, MBA, Miami Cancer Institute, Baptist Health South Florida

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

August 12, 2022

Primary Completion (Estimated)

June 1, 2027

Study Completion (Estimated)

December 1, 2027

Study Registration Dates

First Submitted

March 1, 2022

First Submitted That Met QC Criteria

March 31, 2022

First Posted (Actual)

April 8, 2022

Study Record Updates

Last Update Posted (Actual)

August 19, 2026

Last Update Submitted That Met QC Criteria

August 17, 2026

Last Verified

August 1, 2026

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • BT012

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

Yes

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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