Focused Ultrasound + Chemotherapy for Pediatric Brain Cancer

Overseen By Nadir Alikacem

Age: < 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: InSightec

Must not be taking: Anthracyclines, NSAIDs, Statins, others

Disqualifiers: Infection, Seizure disorder, HIV, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 12-18 weeks

10 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment for pediatric brain cancer using a combination of focused ultrasound and the chemotherapy drug Doxorubicin. The goal is to determine if this method can safely and effectively help children with a specific type of brain tumor called DIPG. The treatment aims to open the blood-brain barrier, allowing the chemotherapy to work more effectively. Children diagnosed with DIPG who have completed radiation therapy might be suitable candidates for this trial. As a Phase 1 and Phase 2 trial, it focuses on understanding the treatment's mechanism and measuring its effectiveness in an initial group, offering participants a chance to contribute to groundbreaking research.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications, but it mentions a washout period for anti-coagulant therapy and medications that increase the risk of bleeding. If you are on such medications, you may need to stop them before starting the trial.

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

Research shows that the combination of Exablate and Doxorubicin is in the early stages of testing for safety in humans. This treatment aims to help children with brain tumors by using focused ultrasound to assist Doxorubicin, a chemotherapy drug, in crossing the blood-brain barrier, which protects the brain.

Since the treatment is still in early clinical trials, researchers are evaluating how well patients tolerate it and what side effects might occur. It is not yet approved, so ongoing studies closely examine its safety.

Other studies suggest that using Exablate to open the blood-brain barrier is promising, but researchers must continue monitoring for any negative effects. Participants in these trials help researchers understand the potential risks and benefits to ensure safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about using Focused Ultrasound combined with Doxorubicin for treating pediatric brain cancer because it offers a novel way to breach the blood-brain barrier (BBB). Unlike standard treatments, which often struggle to deliver drugs effectively to brain tumors, this method uses Exablate MR Guided Focused Ultrasound to temporarily open the BBB, allowing more Doxorubicin to reach the tumor. This innovative approach could enhance the drug's effectiveness and potentially reduce side effects associated with higher doses of chemotherapy.

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

In this trial, participants will receive treatment using Exablate MR Guided Focused Ultrasound with Doxorubicin to help treat diffuse intrinsic pontine gliomas (DIPG), a serious type of children's brain cancer. The Exablate system temporarily opens the blood-brain barrier, which usually protects the brain but can also block helpful treatments. By opening this barrier, Doxorubicin, a chemotherapy drug, can reach the tumor more effectively. Early studies have shown promise in using this method to target and treat brain tumors. This combination might improve the drug's ability to reach the cancerous area, which is usually hard to access. ^{1 2 3 4 5}

Are You a Good Fit for This Trial?

This trial is for children aged 5-18 with DIPG who've finished radiation therapy within the last 3 months and show no post-radiation complications. They must be stable after any brain surgery, not on increasing steroids, able to attend visits, expected to live at least 6 more months, and have consent from a guardian.

Inclusion Criteria

Able to attend all study visits and with life expectancy of at least 6 months

Able and willing to give consent and/or assent or have a legal guardian who is able and willing to do so

It's been over 2 weeks since my brain surgery, and I've fully recovered without any neurological issues.

Exclusion Criteria

I have an infection in my brain or elsewhere in my body.

I have a history of bleeding disorders or my tumor has bled on its own.

The tumor cannot be seen on any imaging before or after radiation treatment.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants undergo 3 cycles of Blood Brain Barrier Disruption using Exablate MR Guided Focused Ultrasound in combination with Doxorubicin, approximately 4-6 weeks apart

12-18 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

What Are the Treatments Tested in This Trial?

Interventions

• Doxorubicin
• Exablate

Trial Overview The study tests if using Exablate focused ultrasound can safely open the blood-brain barrier in combination with Doxorubicin chemotherapy to treat pediatric DIPG. The goal is to see if this method improves treatment effectiveness.

How Is the Trial Designed?

Group I: Blood Brain Barrier Disruption (BBBD) Experimental Treatment 2 Interventions

Exablate MR Guided Focused Ultrasound for Blood Brain Barrier Disruption with Doxorubicin for treating pediatric patients with DIPG

Doxorubicin is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Adriamycin for:

• Breast cancer
• Ovarian cancer
• Bladder cancer
• Lymphomas
• Leukemias
• Multiple myeloma
• Kaposi's sarcoma
• Soft tissue sarcomas

Approved in European Union as Doxorubicin for:

• Breast cancer
• Ovarian cancer
• Bladder cancer
• Lymphomas
• Leukemias
• Multiple myeloma
• Kaposi's sarcoma
• Soft tissue sarcomas

Approved in Canada as Doxorubicin for:

• Breast cancer
• Ovarian cancer
• Bladder cancer
• Lymphomas
• Leukemias
• Multiple myeloma
• Kaposi's sarcoma
• Soft tissue sarcomas

Approved in Japan as Doxorubicin for:

• Breast cancer
• Ovarian cancer
• Bladder cancer
• Lymphomas
• Leukemias
• Multiple myeloma
• Kaposi's sarcoma
• Soft tissue sarcomas

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

The study introduces a novel drug delivery system using ultrasound-sensitive emulsion liposomes (eLiposomes) that effectively release the anticancer drug doxorubicin (Dox) when exposed to low-intensity ultrasound, particularly at 20 kHz.

This targeted delivery method not only enhances the localized treatment of tumors but also has the potential to minimize the cardiotoxic side effects typically associated with doxorubicin, making it a promising approach for cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ultrasound sensitive eLiposomes containing doxorubicin for drug targeting therapy. Lin, CY., Javadi, M., Belnap, DM., et al.[2022]

The study demonstrated that using focused ultrasound (FUS) to disrupt the blood-brain barrier significantly enhances the accumulation of targeted doxorubicin liposomes in brain tumors, improving drug delivery in tumor-bearing mice.

Targeted liposomes (AP-1 Lipo-Dox) showed the highest tumor-to-normal brain drug ratio when combined with FUS, indicating a promising approach for optimizing chemotherapy for brain tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetic analysis of 111 in-labeled liposomal Doxorubicin in murine glioblastoma after blood-brain barrier disruption by focused ultrasound. Yang, FY., Wang, HE., Liu, RS., et al.[2021]

The study developed bFGF-DOX-MB microbubbles, which are doxorubicin-loaded particles that target tumors effectively, showing an average size of 2.7 μm.

In an A549 mouse model, the combination of bFGF-DOX-MB with ultrasound significantly inhibited tumor growth compared to other treatment groups, suggesting that this method could enhance the effectiveness of chemotherapy through targeted delivery and ultrasound assistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preparation and antitumor activity of bFGF-mediated active targeting doxorubicin microbubbles. Wu, Y., Lu, CT., Li, WF., et al.[2013]

A noninvasive method using MRI-guided focused ultrasound successfully delivered therapeutic levels of doxorubicin (DOX) through the blood-brain barrier in rats, achieving concentrations of 886 ng/g tissue with minimal damage.

Higher doses of the ultrasound technique resulted in even greater DOX levels (up to 5,366 ng/g), but with increased tissue damage, indicating a balance between efficacy and safety in targeted chemotherapy for brain tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeted delivery of doxorubicin to the rat brain at therapeutic levels using MRI-guided focused ultrasound. Treat, LH., McDannold, N., Vykhodtseva, N., et al.[2022]

Focused ultrasound (FUS) combined with microbubbles significantly enhances the permeability of the blood-tumor barrier (BTB), allowing for increased delivery of liposomal doxorubicin to brain tumors in a rat glioma model, with drug concentrations more than double those in control tumors.

The study demonstrated that FUS-induced drug delivery enhancements are consistent over time, suggesting that even large or late-stage tumors can benefit from this method, although the effectiveness of MRI contrast agents may need to be reconsidered for optimal evaluation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enhancement in blood-tumor barrier permeability and delivery of liposomal doxorubicin using focused ultrasound and microbubbles: evaluation during tumor progression in a rat glioma model. Aryal, M., Park, J., Vykhodtseva, N., et al.[2018]

Focused ultrasound (FUS) can safely open the blood-brain barrier (BBB) to enhance the delivery of doxorubicin-loaded cationic liposomes (DOX-CLs) to glioma tumors, significantly improving drug accumulation in tumor tissues.

In vivo studies showed that the combination of FUS and DOX-CLs not only inhibited glioma progression effectively but also extended animal survival time to an average of 81.2 days, indicating a promising strategy for future brain tumor therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brain tumor-targeted delivery and therapy by focused ultrasound introduced doxorubicin-loaded cationic liposomes. Lin, Q., Mao, KL., Tian, FR., et al.[2018]

Using focused ultrasound (FUS) to disrupt the blood-brain barrier (BBB) significantly increased the concentration of doxorubicin (Dox) in glioblastoma multiforme (GBM) tumors, achieving a 2.35-fold higher tumor-to-normal brain Dox ratio compared to controls.

The peak concentration of Dox in the sonicated tumors was 10 times greater than in non-sonicated tumors, indicating that FUS can enhance drug delivery to brain tumors, which could improve treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of doxorubicin in glioblastoma multiforme following ultrasound-Induced blood-brain barrier disruption as determined by microdialysis. Lin, YL., Wu, MT., Yang, FY.[2018]

Using focused ultrasound (FUS) to enhance the delivery of liposomal doxorubicin significantly reduced tumor growth in rats with brain tumors compared to doxorubicin treatment alone, indicating improved drug delivery across the blood-brain barrier.

The combination of FUS and doxorubicin treatment resulted in a modest but significant increase in median survival time for the rats, suggesting that this method could enhance the effectiveness of chemotherapy for brain tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improved anti-tumor effect of liposomal doxorubicin after targeted blood-brain barrier disruption by MRI-guided focused ultrasound in rat glioma. Treat, LH., McDannold, N., Zhang, Y., et al.[2022]

The novel FH peptide-modified ultrasonic nanobubbles (FH-NB-DOX) effectively target cancer-associated fibroblasts (CAFs) due to their ability to bind to the tenascin C protein, which is highly expressed in these cells.

Under ultrasound irradiation, FH-NB-DOX demonstrated superior delivery of the chemotherapy drug doxorubicin (DOX) into CAFs, leading to more effective cancer cell eradication compared to standard doxorubicin formulations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New FH peptide-modified ultrasonic nanobubbles for delivery of doxorubicin to cancer-associated fibroblasts. Guo, L., Shi, D., Meng, D., et al.[2020]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05630209

Study Details | NCT05630209 | Blood Brain Barrier (BBB) ... The purpose of this study is to evaluate the safety and efficacy of targeted blood brain barrier disruption with Exablate Model 4000 Type2.0/2.1 in combination ...

2. connect.careboxhealth.com connect.careboxhealth.com/en-US/trial/listing/371675

Blood Brain Barrier (BBB) Disruption Using Exablate Focused ... The purpose of this study is to evaluate the safety and efficacy of targeted blood brain barrier disruption with Exablate Model 4000 Type2.0/2.1 in ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT05615623?cond=Brain%20Tumor&term=focused%20ultrasound&aggFilters=status:not%20rec&rank=1

Blood Brain Barrier (BBB) Disruption Using Exablate ... The study aims to establish feasibility and safety of Exablate BBBD in conjunction with Doxorubicin in the treatment of pediatric DIPG and assess preliminary ...

4. trials.braintumor.org trials.braintumor.org/trials/NCT05615623

Blood Brain Barrier (BBB) Disruption Using Exablate Focused ... Blood Brain Barrier Disruption (BBBD) via Exablate Type 2 system with microbubble resonators on the day of Doxorubicin infusion to treat DIPG brain tumors.

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10842695/

Targeting Diffuse Midline Gliomas: The Promise of Focused ... Diffuse midline gliomas (DMGs), including diffuse intrinsic pontine glioma, have among the highest mortality rates of all childhood cancers, despite recent ...