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

Trial Summary

What is the purpose of this trial?

The purpose of this study is to evaluate the safety and efficacy of targeted blood brain barrier disruption with Exablate Model 4000 Type 2.0/2.1 in combination with Doxorubicin therapy for the treatment of DIPG in pediatric patients

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.

What evidence supports the effectiveness of the treatment for pediatric brain cancer?

Research shows that using focused ultrasound to temporarily open the blood-brain barrier can significantly enhance the delivery and effectiveness of doxorubicin, a chemotherapy drug, in treating brain tumors. Studies in animal models have demonstrated that this combination can reduce tumor growth and improve survival rates 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, a chemotherapy drug, can increase its effectiveness in treating brain tumors in animal models. While this method can achieve therapeutic drug levels in the brain, higher doses may cause tissue damage, indicating a need for careful dose management to ensure safety. ^{1 2 3 6 7}

What makes the treatment of focused ultrasound and doxorubicin unique for pediatric brain cancer?

This treatment is unique because it uses focused ultrasound to temporarily open the blood-brain barrier (a protective layer that prevents many drugs from entering the brain), allowing doxorubicin, a chemotherapy drug, to reach and treat brain tumors more effectively. This approach enhances the drug's ability to target brain cancer cells, potentially improving treatment outcomes compared to traditional methods that struggle to deliver drugs past the blood-brain barrier. ^{1 2 3 8 9}

Eligibility Criteria

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

I am between 5 and 18 years old.

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 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

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

Treatment Details

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.

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]

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]

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]

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]

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]

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]

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. England pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of doxorubicin in glioblastoma multiforme following ultrasound-Induced blood-brain barrier disruption as determined by microdialysis. [2018]

5. England 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. [2018]

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. Germany pubmed.ncbi.nlm.nih.gov

Brain tumor-targeted delivery and therapy by focused ultrasound introduced doxorubicin-loaded cationic liposomes. [2018]

9. 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]