Panobinostat Infusion for Medulloblastoma

Overseen By Bangning Yu, MD, PhD

Age: Any Age

Sex: Any

Trial Phase: Phase < 1

Sponsor: The University of Texas Health Science Center, Houston

Disqualifiers: Other protocol, Infection, Pregnant, 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: Unknown

Duration: 6 weeks

2 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires a minimum of 7 days between your last dose of systemic chemotherapy or radiation therapy and the first infusion of the trial medication. It doesn't specify about other medications, so it's best to discuss with the trial team.

What data supports the effectiveness of the drug Panobinostat for treating medulloblastoma?

Research shows that Panobinostat, when used in preclinical models, has limited penetration into the brain due to barriers like the blood-brain barrier, which may affect its effectiveness depending on the tumor's location. However, studies in other conditions, like diffuse intrinsic pontine glioma, have explored its safety and distribution, suggesting potential for use in brain tumors with alternative delivery methods. ^{1 2 3 4 5}

How is the drug Panobinostat unique in treating medulloblastoma?

Panobinostat is unique because it is a pan-deacetylase inhibitor that works by increasing the acetylation of proteins involved in cancer cell growth and survival, and it is administered intravenously, which is different from many standard oral chemotherapy treatments for medulloblastoma. ^{3 6 7 8 9}

What is the purpose of this trial?

The purpose of this study is to establish the safety of infusions of panobinostat (MTX110) into the fourth ventricle of the brain or tumor resection cavity in patients with recurrent medulloblastoma and to assess the antitumor activity of simultaneous infusions of panobinostat (MTX110) into the fourth ventricle of the brain or resection cavity in patients with recurrent medulloblastoma based upon MRI scans and lumbar cerebrospinal fluid (CSF) cytology.

Research Team

David IIan Sandberg, MD

Principal Investigator

The University of Texas Health Science Center, Houston

Eligibility Criteria

This trial is for children and adults with recurrent medulloblastoma, a type of brain cancer. Participants must have stable neurological conditions, adequate liver function (with consultations if needed), and agree to an implanted catheter for treatment delivery. Pregnant or lactating women, those on other trials, or recently treated with chemotherapy/radiation are excluded.

Inclusion Criteria

My blood tests show enough neutrophils, platelets, and hemoglobin.

I had my last cancer treatment at least a week ago.

My neurological symptoms have been stable for at least a week.

Exclusion Criteria

Pregnant or lactating women

Enrolled in another treatment protocol

Evidence of untreated infection

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive infusions of panobinostat (MTX110) into the fourth ventricle or tumor resection cavity

6 weeks

Regular infusions

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 months

MRI and lumbar CSF cytology assessments

Treatment Details

Interventions

• MTX110

Trial Overview The study tests the safety and tumor-fighting ability of panobinostat (MTX110) infusions directly into the fourth ventricle or resection cavity in the brain. The effectiveness will be monitored through MRI scans and cerebrospinal fluid analysis.

Participant Groups

Group I: Treatment with MTX110 Experimental Treatment 1 Intervention

MTX110 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?

The University of Texas Health Science Center, Houston

Lead Sponsor

Trials

974

Recruited

361,000+

Midatech Pharma plc

Collaborator

Trials

1

Recruited

2+

Findings from Research

In a phase I study involving 9 pediatric patients with refractory solid tumors, panobinostat was administered at a tolerated dose of 15 mg/m2, showing significant biological effects by inducing acetylation of histones H3 and H4, which is important for gene regulation.

While the treatment was generally tolerated, notable adverse effects included Grade 3-4 thrombocytopenia in 33% of patients and Grade 4 drug-related pain in another 33%, indicating the need for careful monitoring of side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I study of panobinostat in pediatric patients with refractory solid tumors, including CNS tumors. Wood, PJ., Strong, R., McArthur, GA., et al.[2019]

The study determined that the maximum tolerated dose of oral panobinostat is 10 mg taken three times weekly when combined with paclitaxel and carboplatin, with myelosuppression being the main dose-limiting toxicity observed in 21 patients.

Despite significant hematologic toxicities like neutropenia and thrombocytopenia, the treatment showed efficacy with three patients achieving partial responses and eleven others maintaining stable disease, indicating potential benefits for patients with advanced solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I trial of oral administration of panobinostat in combination with paclitaxel and carboplatin in patients with solid tumors. Jones, SF., Infante, JR., Thompson, DS., et al.[2018]

UAB30, a novel synthetic rexinoid, significantly reduced cell viability, proliferation, migration, and invasion in group 3 medulloblastoma patient-derived xenografts (PDXs), indicating its potential as an effective treatment.

In vivo studies showed that UAB30 treatment led to a significant decrease in tumor growth and metastasis in mice with medulloblastoma PDXs, similar to the effects of 13-cis-retinoic acid, suggesting its therapeutic promise for this aggressive cancer type.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

UAB30, a novel RXR agonist, decreases tumorigenesis and leptomeningeal disease in group 3 medulloblastoma patient-derived xenografts. Garner, EF., Stafman, LL., Williams, AP., et al.[2020]

The study involved 7 patients with newly diagnosed diffuse intrinsic pontine glioma (DIPG) who received a total of 48 infusions of MTX110 via convection-enhanced delivery (CED), showing that this method is tolerable with manageable side effects, primarily transient neurological issues.

The median overall survival for patients was 26.1 months, which is promising compared to historical data for DIPG, suggesting that further research into this treatment strategy is warranted.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PNOC015: Repeated convection-enhanced delivery of MTX110 (aqueous panobinostat) in children with newly diagnosed diffuse intrinsic pontine glioma. Mueller, S., Kline, C., Stoller, S., et al.[2023]

Panobinostat, a pan-histone deacetylase inhibitor, shows limited central nervous system (CNS) delivery due to the action of efflux transporters P-glycoprotein and breast cancer resistant protein, which may hinder its effectiveness against CNS tumors.

The study found that panobinostat's distribution in the brain is heterogeneous, meaning its efficacy could vary based on tumor location, suggesting that alternative delivery methods may be needed to improve treatment outcomes for pediatric brain tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Central Nervous System Distribution of Panobinostat in Preclinical Models to Guide Dosing for Pediatric Brain Tumors. Zhang, W., Oh, JH., Zhang, W., et al.[2023]

The maximum tolerated dose (MTD) of intravenous panobinostat was determined to be 7.2 mg/m² for daily administration and 20.0 mg/m² for weekly administration in patients with advanced solid tumors or lymphoma, indicating a clear dosing strategy for future studies.

While the intravenous formulation of panobinostat was generally well tolerated, safety concerns such as fatigue, cardiac arrhythmias, and myelosuppressive effects suggest that further development will focus on an oral formulation to mitigate these risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I dose-escalation study of intravenous panobinostat in patients with lymphoma and solid tumors. Sharma, S., Beck, J., Mita, M., et al.[2022]

In a Phase I study involving 14 Japanese patients with advanced solid tumors, intravenous panobinostat was found to have a maximum tolerated dose (MTD) of 20 mg/m², with dose-limiting toxicity observed in one patient.

While thrombocytopenia (low platelet count) was common and severe in some cases, it resolved quickly, and the treatment showed some antitumor activity with stable disease in six patients for at least four months, although no complete or partial responses were recorded.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I dose-escalating study of panobinostat (LBH589) administered intravenously to Japanese patients with advanced solid tumors. Morita, S., Oizumi, S., Minami, H., et al.[2021]

Metastatic medulloblastoma is rare, but when it occurs, various chemotherapy regimens can provide palliative care.

In the authors' experience, specific combinations like vincristine-actinomycin-D-cyclophosphamide (VAC) showed two objective responses, indicating potential efficacy in treating this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chemotherapeutic response in metastatic medulloblastoma: report of two cases and a review of the literature. Nathanson, L., Kovacs, SG.[2019]

In a study of 60 Chinese children with relapsed medulloblastoma, the use of intrathecal methotrexate (IT-MTX) significantly improved overall survival (OS) and progression-free survival (PFS) rates, with 5-year OS rates of 49.5% for IT-MTX users compared to 14.6% for those who did not receive it.

The median survival time after relapse was 2.8 years, but the presence of tumor cells in the cerebrospinal fluid was associated with shorter survival rates, highlighting the importance of monitoring and treating this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Characteristics and Outcome of Children With Relapsed Medulloblastoma: A Retrospective Study at a Single Center in China. Du, S., Yang, S., Zhao, X., et al.[2019]

References

1. Germany pubmed.ncbi.nlm.nih.gov

A phase I study of panobinostat in pediatric patients with refractory solid tumors, including CNS tumors. [2019]

2. Germany pubmed.ncbi.nlm.nih.gov

A phase I trial of oral administration of panobinostat in combination with paclitaxel and carboplatin in patients with solid tumors. [2018]

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

UAB30, a novel RXR agonist, decreases tumorigenesis and leptomeningeal disease in group 3 medulloblastoma patient-derived xenografts. [2020]

4. England pubmed.ncbi.nlm.nih.gov

PNOC015: Repeated convection-enhanced delivery of MTX110 (aqueous panobinostat) in children with newly diagnosed diffuse intrinsic pontine glioma. [2023]

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

Central Nervous System Distribution of Panobinostat in Preclinical Models to Guide Dosing for Pediatric Brain Tumors. [2023]

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

A phase I dose-escalation study of intravenous panobinostat in patients with lymphoma and solid tumors. [2022]

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

Phase I dose-escalating study of panobinostat (LBH589) administered intravenously to Japanese patients with advanced solid tumors. [2021]

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

Chemotherapeutic response in metastatic medulloblastoma: report of two cases and a review of the literature. [2019]

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

Clinical Characteristics and Outcome of Children With Relapsed Medulloblastoma: A Retrospective Study at a Single Center in China. [2019]