Methotrexate + Etoposide for Recurrent Brain Cancer

Overseen By Bangning L Yu, RN, PhD

Age: Any Age

Sex: Any

Trial Phase: Phase < 1

Sponsor: The University of Texas Health Science Center, Houston

Disqualifiers: Other treatment protocol, Infection, Pregnancy, others

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

Compensation: Varies

Number of Visits: 16

Duration: 6 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety of administering two drugs, methotrexate and etoposide, directly into the brain to treat recurring brain cancer. It focuses on aggressive tumors that return after treatment, such as medulloblastoma and ependymoma, particularly when they originate in the brain's posterior fossa. Suitable participants have experienced a recurrence of these tumors and have an Ommaya reservoir implanted to deliver the medicine directly into the brain. The trial aims to determine if this method is safe and effective in managing these challenging tumors. As an Early Phase 1 trial, this research seeks to understand how the treatment works in people, offering participants a chance to contribute to groundbreaking cancer research.

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 drugs. It does not specify about other medications, so it's best to discuss your current medications with the trial team.

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

Research shows that methotrexate, one of the treatments in this trial, is often used for various cancers, including brain tumors, and has a well-known safety record. Previous studies have safely administered methotrexate directly into the brain to treat conditions like medulloblastoma and ependymoma.

Etoposide, the other treatment being tested, is also used in cancer care. While the combination of methotrexate and etoposide remains under study, methotrexate alone has demonstrated safety when used similarly. This early-stage trial aims to assess the safety of using these drugs together directly in the brain.

As an early phase trial, the primary goal is to gather initial safety information. The researchers aim to ensure that using these treatments together in this manner is safe for participants. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about the methotrexate and etoposide treatment for recurrent brain cancer because it offers a unique delivery method. Unlike standard treatments like surgery or systemic chemotherapy, this approach directly infuses the medications into the fourth ventricle of the brain via an Ommaya reservoir, potentially increasing drug concentration at the tumor site while minimizing systemic side effects. Methotrexate and etoposide are both well-known cancer drugs, but their targeted delivery through an intraventricular infusion is what sets this treatment apart, offering hope for more efficient and effective management of brain cancer recurrence.

What evidence suggests that methotrexate and etoposide might be effective treatments for recurrent brain cancer?

Research has shown that methotrexate combined with etoposide can help treat certain brain tumors. In this trial, participants will receive methotrexate and etoposide through intraventricular infusions. Methotrexate, often administered in high doses, plays a crucial role in treating cancers of the brain and spinal cord. The combination of methotrexate and etoposide has shown promise, particularly for patients with specific brain tumors. Previous studies suggest that this combination can effectively target tumor cells. Although more research is needed for this specific application, current evidence offers hope for individuals with recurring brain cancer. ^{1 5 6 7 8}

Who Is on the Research Team?

David Sandberg, MD

Principal Investigator

UTHealth

Are You a Good Fit for This Trial?

This trial is for children and adults aged 1-80 with recurrent malignant brain tumors in the posterior fossa, including medulloblastoma and ependymoma. Participants must have a life expectancy of at least 12 weeks, stable neurological deficits for a week before joining, adequate bone marrow function, an Ommaya reservoir or agree to have one placed, and not be on other treatment protocols.

Inclusion Criteria

Patient must have either measurable or evaluable tumor as assessed by MRI of the brain and total spine

My cancer started in the back part of my brain and has come back or gotten worse.

I have recovered from side effects of my previous cancer treatments.

Exclusion Criteria

I haven't had any experimental treatments or chemotherapy within the last week.

Pregnant or lactating women

Evidence of untreated infection

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Surgical Catheter Placement

Surgery to place a catheter into the Ommaya reservoir for drug administration

1 week

1 visit (in-person)

Treatment

Participants receive intraventricular infusions of Methotrexate and Etoposide

6 weeks

12 visits (in-person) for Methotrexate, 15 visits (in-person) for Etoposide

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

2 visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Etoposide
• Methotrexate
• Ommaya Reservoir

Trial Overview The study tests the safety of infusing methotrexate and etoposide directly into the fourth ventricle or tumor cavity in the brain using an Ommaya reservoir. It targets patients whose cancer has returned after previous treatments. The aim is to see if this method can control tumor growth more effectively.

How Is the Trial Designed?

Group I: Methotrexate / Etoposide Infusion Experimental Treatment 3 Interventions

12 infusions of intraventricular Methotrexate and 15 infusions of intraventricular Etoposide into implanted fourth ventricle catheter/Ommaya reservoir following surgical catheter placement into fourth ventricle. Methotrexate will be infused twice weekly for 6 weeks and etoposide will be infused 5 times a week on weeks 1, 3 , and 5.

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

Approved in United States as Etoposide for:

• Testicular cancer
• Small cell lung cancer
• Non-Hodgkin lymphoma
• Acute myeloid leukemia

Approved in European Union as Etoposide for:

• Testicular cancer
• Small cell lung cancer
• Non-Hodgkin lymphoma
• Acute myeloid leukemia

Approved in Canada as Etoposide for:

• Testicular cancer
• Small cell lung cancer
• Non-Hodgkin lymphoma
• Acute myeloid leukemia

Who Is Running the Clinical Trial?

The University of Texas Health Science Center, Houston

Lead Sponsor

Trials

974

Recruited

361,000+

Published Research Related to This Trial

In a study of seven patients aged 4 to 16 with recurrent medulloblastoma, low-dose oral VP-16 (etoposide) showed promising activity, with six patients achieving partial responses and one maintaining stable disease after treatment.

The treatment was generally well tolerated, although it did cause hematologic toxicity, including neutropenia and thrombocytopenia, but there were no treatment-related deaths, indicating a potential safe option for heavily pretreated patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Response of recurrent medulloblastoma to low-dose oral etoposide. Ashley, DM., Meier, L., Kerby, T., et al.[2017]

In a study involving high-dose methotrexate (MTX) therapy combined with etoposide for treating medulloblastoma, the timing of etoposide administration significantly affected toxicity levels, with more severe side effects observed when etoposide was given 24 and 48 hours after starting MTX.

The study found that administering etoposide before and after MTX resulted in lower toxicity and only a slight decrease in MTX elimination, suggesting that the timing of drug administration can influence the pharmacokinetics of MTX and the overall safety of the treatment protocol.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of etoposide on the pharmacokinetics of methotrexate in vivo. Paál, K., Horváth, J., Csáki, C., et al.[2019]

In a study of 12 patients with recurrent brainstem gliomas, the oral topoisomerase inhibitor VP-16 (Etoposide) showed promising results, with 6 patients demonstrating a radiographic response, including 1 complete response and 3 partial responses, and a median duration of response of 8 months.

VP-16 was well tolerated with manageable side effects, such as partial alopecia and diarrhea, and no treatment-related deaths, indicating its relative safety as a chemotherapy option for this patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recurrent brainstem gliomas treated with oral VP-16. Chamberlain, MC.[2019]

Chronic oral VP-16 (Etoposide) was administered to 8 patients with locally recurrent medulloblastoma, showing that it is a well-tolerated chemotherapy option with manageable side effects, including partial alopecia and neutropenia.

Out of the 8 patients, 62.5% experienced either stable disease or partial responses lasting between 4 to 10 months, indicating that VP-16 has potential efficacy in treating this type of brain tumor.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chronic oral VP-16 for recurrent medulloblastoma. Chamberlain, MC., Kormanik, PA.[2019]

Methotrexate-loaded nanoparticles, especially those conjugated with an ApoE mimicking peptide, showed improved targeting and distribution in the brain, indicating a promising approach for glioma treatment.

In vivo studies on glioma models demonstrated that these nanoparticles significantly slowed tumor growth and induced apoptosis in cancer cells, suggesting their potential efficacy in treating glioblastoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Solid lipid nanoparticles by coacervation loaded with a methotrexate prodrug: preliminary study for glioma treatment. Battaglia, L., Muntoni, E., Chirio, D., et al.[2017]

In a study of 22 patients with recurrent malignant brain tumors, etoposide (VP-16-213) showed a 17% response rate, with three patients experiencing significant clinical improvement lasting from two to over 21 months.

The treatment was well tolerated, and while etoposide was found in very low concentrations in cerebrospinal fluid (less than 1% of plasma levels), it still demonstrated potential efficacy in patients resistant to other therapies, suggesting a possible role in their treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Etoposide (VP-16-213) in malignant brain tumors: a phase II study. Tirelli, U., D'Incalci, M., Canetta, R., et al.[2017]

In a study of five patients with recurrent medulloblastoma, etoposide treatment led to a complete response in two patients and a partial response in one, indicating its potential efficacy against this type of cancer.

The median survival for patients who responded to etoposide was 19 months, with the three responders living significantly longer, suggesting that etoposide may be an effective treatment option for recurrent medulloblastoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Etoposide treatment in recurrent medulloblastoma. Boor, R., Huber, A., Gutjahr, P.[2013]

In a study involving four pediatric patients with malignant brain tumors, treatment with very high-dose etoposide and cyclophosphamide followed by autologous bone marrow rescue showed promising results, particularly in two patients with brain stem gliomas who experienced clinical improvement and tumor size reduction.

The treatment led to a response duration of three to nine months, and detectable levels of the drugs were found in cerebrospinal fluid, suggesting that further research into this chemotherapy regimen for pediatric brain tumors is warranted.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Effect of high-dose cyclophosphamide plus high-dose etoposide in malignant brain tumors of children followed by autologous bone marrow rescue]. Hanada, R., Inaba, T., Yaginuma, A., et al.[2013]

A case study of a 67-year-old woman with primary central nervous system lymphoma revealed that co-administration of levofloxacin (LVFX) with high-dose methotrexate (MTX) led to elevated serum MTX levels (0.153 µmol/L) 72 hours post-infusion, exceeding the safe threshold.

The findings suggest that LVFX delays the excretion of MTX, highlighting the importance of monitoring serum MTX concentrations during treatment to prevent serious adverse effects from drug interactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Delayed methotrexate elimination in a patient with primary central nervous system lymphoma: A case report. Urata, S., Yoshikawa, N., Saito, K., et al.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9258364/

Intrathecal methotrexate in combination with systemic ... Intrathecal MTX combined with systemic chemotherapy is a potentially effective therapy for GBM patients with LMD. KPS > 60, gross resection of the brain tumor, ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT02905110

NCT02905110 | Methotrexate and Etoposide Infusions Into ... The goal of this clinical research study is to establish the safety of simultaneous infusions of methotrexate and etoposide into the fourth ventricle of the ...

3. researchgate.net researchgate.net/figure/Treatment-HD-high-dose-MTX-methotrexate-VP16-etoposide-CYCLO-cyclophosphamide_fig1_23656164

Treatment. HD, high dose; MTX, methotrexate; VP16 ... The 5-year survival rate of high-risk patients is less than 70% [10, 12, 13]. For the current treatment of MB, in addition to surgical resection, radiotherapy ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5256683/

Methotrexate Re-Challenge for Recurrent Primary Central ... The prognosis of primary CNS lymphoma (PCNSL) recurring after methotrexate is poor (objective response rates [ORR] = 26%–53%; 1-year overall survival [OS] ...

5. ascopubs.org ascopubs.org/doi/pdf/10.1200/EDBK_242547

Evolving Treatments for Primary Central Nervous System ... High-dose methotrexate (MTX) remains a cornerstone of induction regimens, and most data support the use of rituximab. However, clinical research ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7279024/

Overview of Dual-Acting Drug Methotrexate in Different ... MTX is approved also to be used in the treatment of many other types of cancer like brain tumours, breast cancer, hepatoma, lung cancer, lymphomas, certain ...

7. mdpi.com mdpi.com/2072-6694/17/3/439

Advances in the Repurposing and Blood–Brain Barrier ... Feasibility and safety were demonstrated with fourth ventricular infusions of methotrexate for the treatment of medulloblastoma and ependymoma [114]. Clinical ...

8. academic.oup.com academic.oup.com/neuro-oncology/advance-article/doi/10.1093/neuonc/noaf132/8158409

Phase 3 randomized trial of high-dose methotrexate for young ... A phase 3 randomized study evaluating high-dose methotrexate in young children < 36 months old with newly diagnosed high-risk embryonal brain tumors.