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

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

What evidence supports the effectiveness of the drug combination Methotrexate and Etoposide for treating recurrent brain cancer?

Research shows that Etoposide has shown some effectiveness in treating recurrent malignant brain tumors, with a small percentage of patients experiencing improvement or stable disease. Additionally, Etoposide has been used successfully in other brain tumor types, suggesting potential benefits when combined with Methotrexate. ^{1 2 3 4 5}

What safety data exists for the combination of Methotrexate and Etoposide in humans?

The combination of Methotrexate and Etoposide has been studied in patients with medulloblastoma, showing that certain schedules of administration can lead to higher toxicity levels, including severe side effects. Etoposide alone has been associated with mild side effects like hair loss and low white blood cell counts, while Methotrexate can cause serious side effects if not properly eliminated from the body. ^{3 6 7 8 9}

How is the drug combination of Methotrexate and Etoposide unique for treating recurrent brain cancer?

The combination of Methotrexate and Etoposide is unique because it involves using Etoposide, which has shown potential in treating recurrent brain tumors, and Methotrexate, which can enhance the effectiveness of Etoposide by affecting its pharmacokinetics (how the drug moves through the body). This combination may offer a novel approach by potentially improving drug interactions and treatment outcomes for patients with recurrent brain cancer. ^{1 2 3 6 7}

What is the purpose of this trial?

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 brain or resection cavity in patients with recurrent malignant posterior fossa brain tumors. These tumors include medulloblastoma, ependymoma, atypical teratoid/rhabdoid tumor or other malignant brain tumor with recurrence or progression involving anywhere in the brain and/or spine. Patients' disease must have originated in the posterior fossa of the brain.

Research Team

David Sandberg, MD

Principal Investigator

UTHealth

Eligibility Criteria

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

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)

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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 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]

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]

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]

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]

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]

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]

References

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

Etoposide (VP-16-213) in malignant brain tumors: a phase II study. [2017]

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

Response of recurrent medulloblastoma to low-dose oral etoposide. [2017]

3. England pubmed.ncbi.nlm.nih.gov

Effect of etoposide on the pharmacokinetics of methotrexate in vivo. [2019]

4. Japan 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]. [2013]

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

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

6. Germany pubmed.ncbi.nlm.nih.gov

Etoposide treatment in recurrent medulloblastoma. [2013]

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

Chronic oral VP-16 for recurrent medulloblastoma. [2019]

8. England pubmed.ncbi.nlm.nih.gov

Delayed methotrexate elimination in a patient with primary central nervous system lymphoma: A case report. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Solid lipid nanoparticles by coacervation loaded with a methotrexate prodrug: preliminary study for glioma treatment. [2017]