Focused Ultrasound + Immunotherapy for Brain Cancer

(LIMITLESS Trial)

Recruiting at 4 trial locations

Overseen By Nadir Alikacem

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: InSightec

Must be taking: Immune checkpoint inhibitors

Must not be taking: Bevacizumab, Immunosuppressants

Disqualifiers: Intracranial hemorrhage, Infections, Transplants, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 9

Duration: 18 weeks

30 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new method to treat brain cancer that has spread from lung cancer. It combines focused ultrasound, which makes the brain more accessible to treatments, with pembrolizumab, an immune system booster. Researchers aim to determine if this combination is safe and more effective than the drug alone. Individuals with lung cancer that has spread to the brain and are already scheduled for immune therapy might be suitable for this study. As a Phase 3 trial, this treatment is in the final step before FDA approval, offering patients a chance to contribute to potentially groundbreaking advancements in cancer therapy.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are on Bevacizumab (Avastin) or certain immunosuppressive therapies, you may not be eligible to participate.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the Exablate Model 4000 Type 2.0/2.1, which helps open the blood-brain barrier, has undergone safety studies. Some serious side effects may occur and require medical attention, but they are expected and manageable. This device is designed to enhance the delivery of treatments to brain tumors.

Pembrolizumab, the immune therapy used in this trial, has received approval for treating other cancers, indicating it has undergone safety testing in humans. Most individuals tolerate it well, though some may experience side effects such as tiredness or skin problems.

Together, the Exablate system and pembrolizumab aim to improve brain cancer treatment. Previous studies suggest they are generally safe, but, like any treatment, there are risks to consider. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of focused ultrasound and immunotherapy for treating brain cancer because it introduces a novel way to enhance drug delivery to the brain. Unlike traditional treatments, which often struggle to penetrate the blood-brain barrier effectively, this approach uses the Exablate Model 4000 Type 2 to temporarily open this barrier, allowing pembrolizumab, an immunotherapy drug, to reach the tumor more efficiently. This technique could potentially improve the effectiveness of pembrolizumab against brain metastases from non-small cell lung cancer (NSCLC), offering hope for better outcomes in a condition where treatment options are currently limited.

What evidence suggests that this trial's treatments could be effective for brain cancer?

Research shows that the Exablate Model 4000 Type 2.0/2.1 can safely and effectively open the blood-brain barrier, a protective shield around the brain, to help treat brain metastases from non-small cell lung cancer (NSCLC). In this trial, some participants will receive focused ultrasound treatment combined with immune checkpoint inhibitors, such as pembrolizumab, to enhance drug delivery to brain tumors. Studies suggest that this combination has shown promise in improving drug efficacy and overall treatment outcomes. Initial findings are encouraging, indicating that the procedure is feasible and well-tolerated by patients. ^{1 3 6 7 8}

Who Is on the Research Team?

Manmeet Ahluwalia, MD, MBA

Principal Investigator

Miami Cancer Institute, Baptist Health South Florida

Are You a Good Fit for This Trial?

Adults with non-small cell lung cancer (NSCLC) brain metastases, not pregnant, willing to use contraception and comply with study procedures. Must have EGFR/ALK-negative tumors, measurable untreated brain metastasis accessible by MRI, good performance status (Karnofsky ≥70% or ECOG 0-2), and prescribed pembrolizumab. Excludes those with bleeding risks, certain infections like hepatitis/HIV/TB, severe medical disorders, known allergies to trial substances, contraindications to MRI/gadolinium-DTPA or pembrolizumab.

Inclusion Criteria

I am not pregnant and will use effective birth control during and 4 months after the study.

Participant is willing to comply with all study procedures for the duration of the study

I can take care of myself and perform normal activities.

Exclusion Criteria

I am allergic or cannot take pembrolizumab due to severe reactions.

I have not received a live vaccine in the last 28 days.

I have an autoimmune disease treated in the last 2 years or currently have pneumonitis.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive ICI Systemic Therapy with Exablate BBBO or ICI Systemic Therapy alone every 3 weeks for 6 cycles

18 weeks

6 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of tumor response and adverse events

up to 6 months

Every 3 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Exablate Model 4000 Type 2.0/2.1
• Pembrolizumab

Trial Overview The trial is testing the safety and effectiveness of disrupting the blood-brain barrier using Exablate Focused Ultrasound in combination with standard pembrolizumab therapy for treating NSCLC brain metastases. The goal is to see if this approach can improve treatment outcomes.

How Is the Trial Designed?

Group I: ICI Systemic Therapy with Exablate BBBO Experimental Treatment 6 Interventions

Using Exablate Model 4000 Type 2 for the treatment of NSCLC brain metastases in subjects who are undergoing planned ICI Systemic Therapy.

Group II: Control Arm (ICI Systemic Therapy on-label use only) Active Control 5 Interventions

subjects will undergo planned on-label ICI Systemic Therapy.

Pembrolizumab is already approved in United States, European Union, United Kingdom for the following indications:

Approved in United States as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in European Union as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in United Kingdom as KEYTRUDA for:

• Untreated metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1

Who Is Running the Clinical Trial?

InSightec

Lead Sponsor

Trials

92

Recruited

3,800+

Dr. Maurice R. Ferré

InSightec

Chief Executive Officer

MD

Dr. Arjun Desai

InSightec

Chief Medical Officer

MD

Published Research Related to This Trial

In a phase 2 trial involving 36 patients with untreated brain metastases from melanoma or non-small-cell lung cancer (NSCLC), pembrolizumab demonstrated activity, achieving a brain metastasis response in 22% of melanoma patients and 33% of NSCLC patients, with responses being durable for most.

The treatment had an acceptable safety profile, with serious adverse events occurring in a small percentage of patients, indicating that systemic immunotherapy could be a viable option for those with untreated or progressive brain metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial. Goldberg, SB., Gettinger, SN., Mahajan, A., et al.[2022]

Pembrolizumab (KEYTRUDA) was approved by the FDA for treating advanced melanoma, showing an overall response rate of 24% in a trial of 89 patients, with 86% of responses lasting at least 6 months.

While there are potential immune-mediated side effects, the benefits of prolonged tumor response durations were deemed to outweigh these risks, marking an improvement over existing treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma. Chuk, MK., Chang, JT., Theoret, MR., et al.[2021]

Pembrolizumab, an immune checkpoint inhibitor, can cause pneumonitis in 1%-5% of patients, and this case report highlights an atypical presentation of this side effect in a patient with metastatic squamous cell carcinoma.

The patient was successfully treated with steroid therapy after ruling out other potential causes, leading to complete resolution of the pneumonitis, emphasizing the importance of recognizing and managing atypical cases of checkpoint inhibitor-pneumonitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recurrent and atypical immune checkpoint inhibitor-induced pneumonitis. Jeon, WJ., Nguyen, J., Castillo, DR., et al.[2023]

Pembrolizumab (KEYTRUDA) was approved by the FDA for treating unresectable or metastatic melanoma based on two clinical trials involving 1,374 patients, showing significant improvements in overall survival compared to ipilimumab, with hazard ratios indicating a reduced risk of death.

Patients receiving pembrolizumab also experienced significant improvements in progression-free survival, although some immune-mediated adverse reactions like hypothyroidism and pneumonitis were noted, highlighting the importance of monitoring for side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Pembrolizumab for the Treatment of Patients with Unresectable or Metastatic Melanoma. Barone, A., Hazarika, M., Theoret, MR., et al.[2022]

The combination of pembrolizumab, hypofractionated stereotactic irradiation (HFSRT), and bevacizumab was found to be generally safe and well tolerated in 32 patients with recurrent high-grade gliomas, with manageable treatment-related adverse events such as proteinuria and fatigue.

In the bevacizumab-naïve group, 83% of patients showed a complete or partial response, with a median overall survival of 13.45 months, indicating promising preliminary efficacy of this treatment combination.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hypofractionated stereotactic re-irradiation with pembrolizumab and bevacizumab in patients with recurrent high-grade gliomas: results from a phase I study. Sahebjam, S., Forsyth, PA., Tran, ND., et al.[2021]

Pembrolizumab (Keytruda) has been approved by the FDA for treating high-risk, non-muscle invasive bladder cancer (NMIBC) in patients who are unresponsive to BCG therapy and are either ineligible for or have opted not to undergo cystectomy.

This approval specifically targets patients with carcinoma in situ (CIS) with or without papillary tumors, highlighting its role as a treatment option for those with limited surgical options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approves Pembrolizumab for BCG-Unresponsive NMIBC. Wright, KM.[2021]

Pembrolizumab (Keytruda) is the first anti-PD-1 therapy approved in the US for treating advanced malignant melanoma, specifically for patients who have progressed after prior treatments.

It is designed to target the PD-1 protein, enhancing the immune system's ability to fight cancer, and is currently under review for approval in the EU.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab: first global approval. Poole, RM.[2021]

Pembrolizumab, a PD-1 inhibitor used in cancer treatment, can lead to rare but serious immune-related adverse events, including type 1 diabetes mellitus, occurring in about 0.2% of cases.

A review of 42 cases revealed that patients may develop diabetic ketoacidosis during treatment, highlighting the need for blood glucose monitoring and awareness of this potential side effect among clinicians.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Programmed Cell Death-1 Inhibitor-Induced Type 1 Diabetes Mellitus. Clotman, K., Janssens, K., Specenier, P., et al.[2022]

In a randomized trial comparing FDA-approved immune checkpoint inhibitors for advanced melanoma, pembrolizumab showed significantly better treatment outcomes than ipilimumab.

This study is notable as it is the first to directly compare these two therapies as first-line treatments, highlighting pembrolizumab's potential as a more effective option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab superior to ipilimumab in melanoma. [2017]

Pembrolizumab, a PD-1 inhibitor, has demonstrated clinical effectiveness in treating various solid tumors, particularly in patients with PD-L1-positive non-small-cell lung cancer and unresectable/metastatic melanoma.

Early-phase trials and ongoing studies are focused on further confirming the clinical benefits of pembrolizumab in thoracic malignancies, highlighting its potential as a significant treatment option in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. Karim, S., Leighl, N.[2017]

In a phase II trial involving 15 patients with recurrent glioblastoma, pembrolizumab treatment did not lead to significant immune activation within the tumor microenvironment, which was characterized by a lack of T cells and a predominance of CD68+ macrophages.

Despite no treatment-related deaths and a median overall survival of 20 months, the study found that pembrolizumab alone was insufficient to induce a robust immune response in most patients, suggesting that additional strategies may be needed to enhance its efficacy in glioblastoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Window-of-opportunity clinical trial of pembrolizumab in patients with recurrent glioblastoma reveals predominance of immune-suppressive macrophages. de Groot, J., Penas-Prado, M., Alfaro-Munoz, K., et al.[2021]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05317858

NCT05317858 | Blood-brain Barrier (BBB) Opening Using ... 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 ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9660993/

LIMITLESS TRIAL - PMC NSCLC is the most common cause of brain metastases. The Exablate focused ultrasound with circulating microbubble resonators uses the concept of real-time ...

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.TPS2101

A phase 1/2 dose escalation and expansion study of ... A phase 1/2 dose escalation and expansion study of sonodynamic therapy with SONALA-001 in combination with Exablate 4000 Type 2.0 MR-guided ...

4. dana-farber.org dana-farber.org/clinical-trials/20-489

Assessment of Safety and Feasibility of Exablate Type 2 for ... The purpose of this study is to evaluate the safety and feasibility of the Exablate Model 4000 Type 2 system when used as a tool to open the blood-brain ...

5. documentation.insightec.com documentation.insightec.com/media/PUB41002923_Exablate-Neuro-IFP-USA_Rev12_FINAL2.pdf

Exablate Neuro Information for Prescribers USA Exablate Neuro/Exablate Prime. Model. 4000. Cradle Type. 1.0 and 1.1. Application. Neuro ... This data demonstrates that the primary effectiveness ...

6. accessdata.fda.gov accessdata.fda.gov/cdrh_docs/pdf15/P150038S014B.pdf

SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED) Serious anticipated treatment adverse effects of the Exablate Neuro are those which may require medical treatment, may have sequelae, and for which time of ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6703178/

Improving CNS Delivery to Brain Metastases by Blood-Tumor ... Brain metastases encompass nearly 80% of all intracranial tumors. A late stage diagnosis confers a poor prognosis, with patients typically surviving less ...

8. centerwatch.com centerwatch.com/clinical-trials/listings/NCT05317858/blood-brain-barrier-bbb-opening-using-exablate-focused-ultrasound-with-standard-of-care-treatment-of-nsclc-brain-mets

Blood-brain Barrier (BBB) Opening Using Exablate ... The purpose of this study is to evaluate the safety and efficacy of targeted blood brain barrier opening with Exablate Model 4000 Type ...