Focused Ultrasound + Chemotherapy for Pediatric Brain Tumor

Recruiting at 1 trial location

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

Trial Summary

What is the purpose of this trial?

This trial is testing a new way to treat children with a difficult-to-treat brain tumor called DIPG. It uses a device to temporarily open the brain's protective barrier so that a cancer drug, Doxorubicin, can enter and target the tumor. The goal is to see if this method is safe and effective. Doxorubicin is a well-known chemotherapy drug, but its effectiveness in treating brain tumors like DIPG has been limited due to the blood-brain barrier.

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.

What data supports the effectiveness of the treatment Focused Ultrasound + Chemotherapy for Pediatric Brain Tumor?

Research shows that using focused ultrasound to temporarily open the blood-brain barrier can enhance the delivery and effectiveness of doxorubicin, a chemotherapy drug, in treating brain tumors. In animal studies, this combination has been shown to reduce tumor growth and increase survival time compared to using doxorubicin alone. ^{1 2 3 4 5}

Is the combination of focused ultrasound and doxorubicin generally safe for humans?

Research shows that using focused ultrasound to help deliver doxorubicin to the brain can achieve therapeutic drug levels with minimal tissue effects, although higher doses may cause more tissue damage. This suggests that the method can be safe, but careful dosing is important to avoid potential harm. ^{1 2 3 6 7}

How does the treatment of focused ultrasound combined with doxorubicin work for pediatric brain tumors?

This treatment uses focused ultrasound to temporarily open the blood-brain barrier (a protective layer that prevents many drugs from entering the brain) so that doxorubicin, a chemotherapy drug, can reach the brain tumor more effectively. This approach aims to enhance the drug's ability to shrink tumors and improve survival compared to using doxorubicin alone. ^{1 2 3 4 8}

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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 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]

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]

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 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 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]

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]

References

1. England 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. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Preparation and antitumor activity of bFGF-mediated active targeting doxorubicin microbubbles. [2013]

3. United States pubmed.ncbi.nlm.nih.gov

Targeted delivery of doxorubicin to the rat brain at therapeutic levels using MRI-guided focused ultrasound. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Pharmacokinetic analysis of 111 in-labeled liposomal Doxorubicin in murine glioblastoma after blood-brain barrier disruption by focused ultrasound. [2021]

5. United States 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. [2023]

6. United States pubmed.ncbi.nlm.nih.gov

Ultrasound sensitive eLiposomes containing doxorubicin for drug targeting therapy. [2022]

7. England pubmed.ncbi.nlm.nih.gov

New FH peptide-modified ultrasonic nanobubbles for delivery of doxorubicin to cancer-associated fibroblasts. [2020]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Evading Doxorubicin-Induced Systemic Immunosuppression Using Ultrasound-Responsive Liposomes Combined with Focused Ultrasound. [2022]