Focused Ultrasound + Chemotherapy for Pediatric Brain Tumor

Recruiting at 3 trial locations

Overseen By Nadir Alikacem

Age: < 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: InSightec

Must not be taking: Bevacizumab, Anticoagulants, NSAIDs, Statins

Disqualifiers: Metastatic disease, Hypertension, Epilepsy, 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 approach for treating a type of pediatric brain tumor called DIPG. Researchers combine a chemotherapy drug, Doxorubicin, with a focused ultrasound technique known as Exablate to enhance the drug's delivery to the brain. The trial aims to determine if this combination is safe and effective for children who have completed radiation therapy. Children diagnosed with DIPG, who have stable neurological status and meet specific recovery conditions post-treatment, may qualify for this trial. As a Phase 1, Phase 2 trial, the research seeks to understand how the treatment works in people and measure its effectiveness in an initial group, offering participants a chance to contribute to groundbreaking advancements in DIPG treatment.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications, but you cannot participate if you are on certain medications like bevacizumab, anti-coagulants, or medications that increase bleeding risk. It's best to discuss your current medications with the trial team.

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

Research has shown that Exablate Focused Ultrasound is being tested for its safety in opening the blood-brain barrier. This method helps deliver treatments directly to brain tumors. Early results suggest it is safe, with no major safety issues reported so far.

Researchers are also studying Doxorubicin, a common cancer treatment. Although effective, it can be harmful if not delivered directly to the tumor. They are exploring the use of focused ultrasound to better target Doxorubicin to brain tumors, aiming to improve safety and reduce side effects.

This trial is in its early stages, so researchers are actively evaluating the safety and tolerability of these treatments for patients. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this treatment because it combines focused ultrasound technology with the chemotherapy drug doxorubicin to treat pediatric brain tumors, specifically DIPG (Diffuse Intrinsic Pontine Glioma). Unlike traditional chemotherapy, which struggles to penetrate the blood-brain barrier, this approach uses Exablate MR Guided Focused Ultrasound to temporarily disrupt this barrier, allowing doxorubicin to reach the tumor more effectively. This innovative delivery method could enhance the drug's impact on the tumor while potentially reducing side effects, offering a promising new avenue for treating this challenging condition.

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

In this trial, participants will receive focused ultrasound to temporarily open the blood-brain barrier, allowing more chemotherapy drugs, such as Doxorubicin, to reach brain tumors. Research has shown that this technique can help the drug enter the central nervous system more effectively. Although this method enhances drug delivery, it has not yet clearly improved survival rates for patients with DIPG, a type of children's brain tumor. The aim is that by delivering more of the drug to the tumor, the treatment might eventually become more effective. Researchers continue to study this approach to understand its full potential. ^{2 4 6 7 8}

Are You a Good Fit for This Trial?

This trial is for pediatric patients aged 5-21 with DIPG who have completed radiation therapy within the last 4-12 weeks and show no signs of necrosis or hemorrhage. They must be neurologically stable, not on increasing steroids, and haven't had brain surgery in the past two weeks. Exclusions include hypertension, contraindications to Doxorubicin, metastatic disease, bleeding disorders, vasculopathy, immunosuppression (except certain steroids), active seizures despite treatment, known sensitivities to specific contrast agents or drugs like Avastin.

Inclusion Criteria

My scans after radiation show no signs of tissue death or bleeding that would prevent focused ultrasound treatment.

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

Exclusion Criteria

I have had seizures that medication couldn't control for at least 4 weeks.

I am not on immunosuppression, except for steroids for brain swelling.

Subject with ventricular peritoneal shunt

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants undergo 3 treatment 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, with adverse events documented and reported

2 years

What Are the Treatments Tested in This Trial?

Interventions

• Doxorubicin
• Exablate

Trial Overview The study tests the safety and effectiveness of disrupting the blood-brain barrier using Exablate Focused Ultrasound (Model 4000 Type2.0/2.1) combined with Doxorubicin chemotherapy for treating pediatric DIPG—a type of brain tumor.

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

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]

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]

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]

Using focused ultrasound (FUS) combined with microbubbles (MBs) significantly enhances the delivery of the chemotherapy drug panobinostat to diffuse intrinsic pontine glioma (DIPG) tumors in mice, resulting in a threefold increase in drug concentration at the tumor site.

The combination treatment led to a 71% reduction in tumor volume and improved survival from 21 to 31 days, demonstrating a promising therapeutic effect against this challenging pediatric brain tumor.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

MRI-Guided Focused Ultrasound Blood-Brain Barrier Opening Increases Drug Delivery and Efficacy in a Diffuse Midline Glioma Mouse Model. Martinez, P., Nault, G., Steiner, J., et al.[2023]

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]

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 introduces a combined therapy using ultrasound-responsive liposomal doxorubicin and focused ultrasound, which reduces the off-target toxicity of doxorubicin on immune cells while maintaining its anticancer effects.

This combined approach not only enhances the infiltration of cytotoxic T lymphocytes into tumors but also improves the overall efficacy of cancer treatment when paired with PD-1 immune-checkpoint blockade therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evading Doxorubicin-Induced Systemic Immunosuppression Using Ultrasound-Responsive Liposomes Combined with Focused Ultrasound. Lee, J., Um, W., Moon, H., et al.[2022]

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. 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 ...

3. 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 ...

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

Blood Brain Barrier (BBB) Disruption Using Exablate Focused ... This is a prospective, single arm, non-randomized feasibility study to evaluate the safety, feasibility and preliminary efficacy of Blood Brain Barrier ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12030708/

PMC Search Update - PubMed Central - NIH Overall, the FUS technique led to an increase in the concentration of the drug in the CNS but did not lead to an improvement in survival in the DIPG xenograft ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7999568/

Doxorubicin-Loaded Gold Nanoarchitectures as a Therapeutic ... Despite its potent antitumour efficacy in multiple cancers, this drug has limited therapeutic efficacy in brain tumours [17,51].

7. fusfoundation.org fusfoundation.org/diseases-and-conditions/diffuse-intrinsic-pontine-glioma-dipg/

Diffuse Intrinsic Pontine Glioma (DIPG) A clinical trial using doxorubicin to treat DIPG has begun in the US. Blood Brain Barrier (BBB) Disruption Using Exablate Focused Ultrasound ...

8. pcrf-kids.org pcrf-kids.org/2023/09/28/focused-ultrasound-offers-hope-for-brain-tumor-patients/

Focused Ultrasound Offers Hope for Brain Tumor Patients Doxorubicin shows promising effects in mouse models of glioma and when delivered directly into tumor tissue, but is too toxic when delivered ...