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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a treatment called MTX110 (also known as Panobinostat) for individuals with medulloblastoma, a type of brain tumor that has recurred or worsened. The main goal is to determine the safety of MTX110 when infused directly into the brain and its effectiveness against the tumor. Participants must have a confirmed medulloblastoma that has returned or progressed and must either have or be willing to have a small device implanted to deliver the treatment. As an Early Phase 1 trial, this research aims to understand how MTX110 works in people, offering participants a chance to be among the first to receive this potentially groundbreaking treatment.

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.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that MTX110, a type of medication, was tested for safety in earlier studies. These studies found that administering MTX110 directly into the brain was generally safe for patients. Doctors conducted check-ups and MRI scans to detect any problems after treatment.

Additionally, research on both short- and long-term use of MTX110 found it to be well-tolerated, indicating that patients did not experience major safety issues. This suggests MTX110 could be a safe option for those considering joining the trial. However, since this trial is in an early stage, the primary goal remains to confirm its safety for this specific use. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for medulloblastoma?

Unlike the standard treatments for medulloblastoma, which typically involve surgery, radiation, and chemotherapy, MTX110 is unique because it is an infusion of panobinostat, a drug that works by inhibiting histone deacetylases (HDACs). This mechanism can potentially stop cancer cells from growing and dividing. Researchers are excited about MTX110 because it offers a targeted approach that might improve outcomes with fewer side effects than traditional methods, possibly enhancing the quality of life for patients.

What evidence suggests that MTX110 might be an effective treatment for medulloblastoma?

Research has shown that MTX110, a form of panobinostat, may help treat medulloblastoma, a type of brain tumor. Studies have found that MTX110 can reduce tumor growth in patient-derived models. Moreover, when combined with radiation, MTX110 slows tumor growth more effectively than either treatment alone. Panobinostat alters the DNA structure of cancer cells, stopping their growth. These early results suggest that MTX110 could be useful in managing recurring medulloblastoma. ^{1 2 6 7 8}

Who Is on the Research Team?

David IIan Sandberg, MD

Principal Investigator

The University of Texas Health Science Center, Houston

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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 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]

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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04315064

Infusion of Panobinostat (MTX110) Into the Fourth Ventricle ... Types of outcome measures include primary outcome measure and secondary outcome measure. ... A type of intervention model describing a clinical trial in which two ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8104457/

High-dose MTX110 (soluble panobinostat) safely ... Panobinostat is a histone deacetylase inhibitor (HDACi) that decreases medulloblastoma tumor growth in orthotopic, patient-derived models. While panobinostat ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8598729/

EXTH-57. EFFICACY OF SOLUBLE PANOBINOSTAT ... In vivo MTX110 in combination with radiation treatment showed an enhanced delay in tumor growth of approximately 50% compared to MTX110 or radiation alone. The ...

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0022356524171248

Central Nervous System Distribution of Panobinostat in ... Panobinostat has heterogeneous distribution into various brain regions, indicating that its efficacy might depend on the anatomical location of the tumors.

5. aacrjournals.org aacrjournals.org/cancerres/article/76/14_Supplement/3198/610463/Abstract-3198-HDAC-inhibitor-panobinostat-as-a

Abstract 3198: HDAC inhibitor panobinostat as a selective ... Medulloblastoma (MB) accounts for over 15% of pediatric brain tumors, with a five-year survival rate of 62%. Neuroblastoma (NB) is the most ...

6. mycancergenome.org mycancergenome.org/content/clinical_trials/NCT04315064/

Clinical Trial: NCT04315064 - Medulloblastoma 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.

7. sigmaaldrich.com sigmaaldrich.com/US/en/tech-docs/paper/1451472?srsltid=AfmBOoq8jbG29HNZfBGSuBZgADSvn29n-HaT0SyVLxcSGf91i3p4YKLd

High-dose MTX110 (soluble panobinostat) safely ... This study tested the safety and pharmacokinetics of short-term and long-term administration of MTX110 (soluble panobinostat; Midatech Pharma) ...

8. withpower.com withpower.com/trial/early-phase-1-medulloblastoma-3-2020-3d36e

Panobinostat Infusion for Medulloblastoma 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 ...