Focused Ultrasound + Panobinostat for Brain Cancer

Recruiting at 2 trial locations

Overseen By Stergios Zacharoulis, MD

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Columbia University

Must be taking: Anticonvulsants

Must not be taking: Anticoagulants

Disqualifiers: Spinal DMGs, Active infection, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 3

Duration: Up to 90 days

3 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial uses sound waves and tiny bubbles to temporarily open the brain's protective barrier, allowing more of the drug Panobinostat to reach brain tumors in children with a specific type of aggressive brain cancer. This method aims to improve treatment response and reduce side effects.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you must be on a stable or decreasing dose of steroids and a stable dose of anti-seizure medication for at least one week before joining. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the treatment Focused Ultrasound + Panobinostat for brain cancer?

Research in mice shows that using focused ultrasound to temporarily open the blood-brain barrier allows more of the drug panobinostat to reach brain tumors, leading to a significant reduction in tumor size and increased survival time. ^{1 2 3 4 5}

Is the combination of Focused Ultrasound and Panobinostat safe for humans?

Panobinostat has been studied in humans for various cancers, and its safety profile is known, with some side effects related to its use. Focused Ultrasound has been used in animal studies to help deliver drugs like Panobinostat to brain tumors, but specific safety data for this combination in humans is not available. ^{1 2 5 6 7}

How does the treatment Focused Ultrasound + Panobinostat differ from other treatments for brain cancer?

This treatment is unique because it uses focused ultrasound to temporarily open the blood-brain barrier, allowing the drug Panobinostat to reach the brain tumor more effectively. This approach aims to improve drug delivery and effectiveness, which is a significant challenge in treating brain cancers due to the protective nature of the blood-brain barrier. ^{1 2 3 8 9}

Research Team

Cheng-Chia Wu, MD, PhD

Principal Investigator

Columbia University

Eligibility Criteria

This trial is for children aged 4-21 with progressive diffuse midline glioma (DMG) who've recovered from prior cancer treatments. They must be able to undergo MRI scans, swallow capsules, and have a stable health condition as assessed by the investigator. Those with spinal DMGs, bleeding disorders, metal implants, or severe systemic diseases are excluded.

Inclusion Criteria

I am between 4 and 21 years old.

My tumor in the brain stem or thalamus is confirmed by imaging or has a specific genetic change.

My brain tumor is growing or spreading.

Exclusion Criteria

Pregnant or breast-feeding women

I am allergic to Panobinostat or similar drugs, or to gadolinium.

I have a bleeding disorder that cannot be corrected.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Focused Ultrasound (FUS) treatment with microbubbles and neuro-navigator-controlled sonication, followed by oral Panobinostat administration

Up to 90 days

Periodic MRIs to confirm BBB opening and closing

Follow-up

Participants are monitored for safety and effectiveness after treatment, including overall survival and progression-free survival

Up to 6 months

Follow-up every 3-6 months

Treatment Details

Interventions

• Focused Ultrasound with neuro-navigator-controlled sonication
• Panobinostat

Trial Overview The study tests if Focused Ultrasound (FUS) can safely open the blood-brain barrier in kids with DMG to enhance Panobinostat delivery to brain tumors. The non-invasive FUS will target up to three areas near the tumor while administering oral Panobinostat.

Participant Groups

Group I: FUS using Oral Panobinostat Experimental Treatment 2 Interventions

All patients enrolled in the study will be treated with oral Panobinostat after receiving Focused Ultrasound treatment (FUS) with microbubbles and neuro-navigator-controlled sonication.

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

Approved in United States as Farydak for:

• Multiple myeloma

Approved in European Union as Farydak for:

• Multiple myeloma

Who Is Running the Clinical Trial?

Columbia University

Lead Sponsor

Trials

1,529

Recruited

2,832,000+

Cheng-Chia (Fred) Wu

Lead Sponsor

Trials

2

Recruited

10+

Focused Ultrasound Foundation

Collaborator

Trials

18

Recruited

460+

Findings from Research

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]

In a study involving 13 adult patients with advanced solid tumors or cutaneous T-cell lymphoma, panobinostat was well tolerated at doses up to 20 mg, with no dose-limiting toxicity observed in 12 evaluable patients.

The most common side effects were diarrhea and nausea, experienced by 76.9% of patients, while thrombocytopenia occurred in 92.3%, indicating a need for monitoring blood cell levels during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I study of oral panobinostat (LBH589) in Japanese patients with advanced solid tumors. Fukutomi, A., Hatake, K., Matsui, K., et al.[2022]

Panobinostat (Farydak(®)) is an HDAC inhibitor that has been approved in the US for use in combination with bortezomib and dexamethasone to treat recurrent multiple myeloma in patients who have undergone at least two prior treatments.

The drug is currently being explored in clinical trials for various hematological and solid tumors, indicating its potential as a versatile cancer treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Panobinostat: first global approval. Garnock-Jones, KP.[2018]

Panobinostat, a histone deacetylase inhibitor for treating relapsed multiple myeloma, primarily undergoes metabolism through the CYP3A4 enzyme, which is crucial for understanding its drug interactions and dosing.

Physiologically based pharmacokinetic (PBPK) modeling predicted that the presence of rifampin, a strong CYP3A4 inducer, could significantly reduce panobinostat exposure by 65%, while its absorption is not affected by changes in stomach pH, leading to important dosing recommendations for clinicians.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Physiologically Based Pharmacokinetic Model Predictions of Panobinostat (LBH589) as a Victim and Perpetrator of Drug-Drug Interactions. Einolf, HJ., Lin, W., Won, CS., et al.[2018]

Diffuse Midline Glioma (DMG), previously known as Diffuse Intrinsic Pontine Glioma (DIPG), is a challenging pediatric brain tumor with no curative treatments available despite over 250 clinical trials.

Focused Ultrasound (FUS) is a promising noninvasive technology that can temporarily disrupt the blood-brain barrier, potentially allowing for better delivery of therapies and enhancing the effectiveness of treatments like chemotherapy and radiation for DMG.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Past, present and future of Focused Ultrasound as an adjunct or complement to DIPG/DMG therapy: A consensus of the 2021 FUSF DIPG meeting. Parekh, K., LeBlang, S., Nazarian, J., et al.[2023]

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]

References

1. 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]

2. England 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]

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

Focused ultrasound disruption of the blood-brain barrier: a new frontier for therapeutic delivery in molecular neurooncology. [2021]

4. Germany pubmed.ncbi.nlm.nih.gov

Panobinostat penetrates the blood-brain barrier and achieves effective brain concentrations in a murine model. [2022]

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

A phase I study of oral panobinostat (LBH589) in Japanese patients with advanced solid tumors. [2022]

6. New Zealand pubmed.ncbi.nlm.nih.gov

Panobinostat: first global approval. [2018]

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

Physiologically Based Pharmacokinetic Model Predictions of Panobinostat (LBH589) as a Victim and Perpetrator of Drug-Drug Interactions. [2018]

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

Past, present and future of Focused Ultrasound as an adjunct or complement to DIPG/DMG therapy: A consensus of the 2021 FUSF DIPG meeting. [2023]

9. 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]