Nivolumab + Methotrexate/5-Azacytidine for Recurrent Brain Tumors

Overseen By Bangning Yu, MD, PhD

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: David Ilan Sandberg

Must not be taking: Corticosteroids

Disqualifiers: Pregnancy, Infection, Stem cell transplant, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 12 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the safety and effects of combining nivolumab, a drug that helps the immune system attack cancer, with two other treatments for brain tumors. It targets patients with recurrent ependymoma using nivolumab and 5-azacytidine (a chemotherapy drug), and those with medulloblastoma or other central nervous system tumors using nivolumab and methotrexate (a chemotherapy drug). The study aims to determine if this combination can enhance the body's immune response to these cancers. Individuals with brain tumors that have returned or are resistant to previous treatments, particularly those located in the back part of the brain (posterior fossa), might be eligible to participate. As a Phase 1 trial, the research focuses on understanding how the treatment works in people.

Do I need to stop my current medications for this trial?

The trial requires that you stop taking corticosteroids at least one week before the first Nivolumab infusion. For other medications, the protocol does not specify, but you may need to stop certain anticancer therapies and investigational agents for a specified period before enrollment.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that nivolumab, combined with either 5-azacytidine or methotrexate, is under study for safety in treating recurring brain tumors. Nivolumab is already approved for other uses, indicating its known safety in humans. However, this trial tests a new delivery method—directly into the brain.

Specific safety information for these drug combinations in this setting is limited because this is an early phase trial. Such trials primarily focus on ensuring human safety and determining the correct dose. While researchers continue to collect safety data, they will closely monitor any serious side effects.

Previous patients using similar treatments have demonstrated that side effects can vary but are usually manageable. The goal is to determine if these drugs can be safely used when delivered directly to the brain and to study any immune responses triggered by nivolumab. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they involve a new delivery method and combination of drugs for treating recurrent brain tumors. Unlike standard treatments, which often include surgery, radiation, and systemic chemotherapy, this approach uses intraventricular infusions, directly delivering the drugs into the brain's ventricles. This method allows high concentrations of the drugs, 5-Azacytidine or Methotrexate, to reach the tumor more effectively, potentially reducing side effects associated with systemic delivery. Additionally, Nivolumab, an immunotherapy drug, is used to stimulate the immune system to attack cancer cells, offering a novel mechanism of action compared to conventional treatments.

What evidence suggests that this trial's treatments could be effective for recurrent brain tumors?

Research has shown that nivolumab can help treat brain metastases, cancers that have spread to the brain. In this trial, one group of participants with recurrent ependymoma will receive a combination of nivolumab and 5-azacytidine. Early results suggest this combination might enhance the immune system's ability to fight the tumor.

For those with medulloblastoma and other CNS malignancies, another group in this trial will receive a combination of nivolumab and methotrexate. High-dose methotrexate has shown promise in treating aggressive brain tumors. By adding nivolumab, researchers aim to boost the body's immune response against the tumor. Overall, these combinations seek to help the immune system better target and fight brain tumors. ^{3 4 6 7 8}

Who Is on the Research Team?

Jeffrey M. Treiber, MD

Principal Investigator

The University of Texas Health Science Center, Houston

Are You a Good Fit for This Trial?

This trial is for people with recurrent brain tumors like medulloblastoma and ependymoma. Participants should have a tumor that can be measured, no prior immunotherapy, and adequate organ function. They must not have an active infection or another cancer, be pregnant, or have had recent surgery.

Inclusion Criteria

I am between 1 and 80 years old and my cancer has come back or gotten worse.

My tumor can be seen or measured on an MRI.

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

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 intraventricular infusions of nivolumab plus 5-azacytidine or methotrexate for 12 weeks

12 weeks

Weekly visits for drug administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• 5-Azacytidine
• Methotrexate
• Nivolumab

Trial Overview

The study tests the safety and tumor-fighting ability of nivolumab (an immune system booster) combined with either methotrexate or 5-azacytidine (chemotherapy drugs), delivered directly into the fourth ventricle of the brain to treat recurring brain tumors.

How Is the Trial Designed?

Group I: Nivolumab plus Methotrexate Experimental Treatment 2 Interventions

Enrolled patients with medulloblastoma and other CNS malignancies will receive: 1. Intraventricular Methotrexate infusions 2 mg daily for 4 consecutive days per week every other week on weeks 1, 3, 5, 7, 9, and 11. 2. Intraventricular Nivolumab infusions. Nivolumab will be administered once every other week on weeks 2, 4, 6, 8, 10, and 12. Dosing will be based upon patient body weight.

Group II: Nivolumab plus 5-Azacytidine Experimental Treatment 2 Interventions

Enrolled patients with ependymoma will receive: 1. Intraventricular 5-Azacytidine infusions 10 mg once weekly for twelve consecutive weeks. 2. Intraventricular Nivolumab infusions once every other week on weeks 1, 3, 5, 7, 9, and 11. Dosing will be based upon patient body weight.

5-Azacytidine is already approved in United States, European Union for the following indications:

Approved in United States as Vidaza for:

• Myelodysplastic syndromes (MDS)
• Acute myeloid leukemia (AML)

Approved in European Union as Vidaza for:

• Myelodysplastic syndromes (MDS)
• Acute myeloid leukemia (AML)
• Chronic myelomonocytic leukemia (CMML)

Approved in United States as Onureg for:

• Acute myeloid leukemia (AML)

Who Is Running the Clinical Trial?

David Ilan Sandberg

Lead Sponsor

Trials

1

Recruited

10+

Peter H. Yang

Lead Sponsor

Trials

1

Recruited

10+

Jeffrey Treiber

Lead Sponsor

Published Research Related to This Trial

In a study involving 91 children with meningeal leukemia, both two-agent (methotrexate and hydrocortisone) and three-agent (adding cytosine arabinoside) intrathecal chemotherapy regimens achieved high rates of complete CNS remission (100% and 96%, respectively).

While the three-agent therapy resulted in a longer median CNS remission duration (64.6 weeks) compared to the two-agent therapy (47.2 weeks), the difference was not statistically significant, and both regimens showed reduced toxicity compared to methotrexate alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination intrathecal therapy for meningeal leukemia: two versus three drugs. Sullivan, MP., Moon, TE., Trueworthy, R., et al.[2021]

In a study of seven patients with CNS lymphoma, the combination of rituximab and temozolomide was well tolerated, with no toxicity reported from rituximab and manageable side effects from temozolomide, indicating a safer alternative to traditional chemotherapy regimens.

The treatment showed promising efficacy, with five patients achieving a complete response and two achieving a partial response, although the median survival was 8 months, suggesting that this regimen could be beneficial for elderly patients with limited treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunochemotherapy with rituximab and temozolomide for central nervous system lymphomas. Wong, ET., Tishler, R., Barron, L., et al.[2018]

In a study involving 4,134 rheumatoid arthritis patients treated with abatacept across seven trials, the incidence of various malignancies was found to be consistent with rates observed in similar RA patients on other treatments, indicating no increased risk associated with abatacept.

The findings suggest that abatacept does not present new safety concerns regarding malignancies, as the observed cancer rates were within the expected range for rheumatoid arthritis populations, and ongoing monitoring will continue.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Malignancies in the rheumatoid arthritis abatacept clinical development programme: an epidemiological assessment. Simon, TA., Smitten, AL., Franklin, J., et al.[2022]

In a phase II study involving 25 patients with newly diagnosed non-AIDS-related primary CNS lymphoma, high-dose intravenous methotrexate (8 g/m²) resulted in a significant radiographic response, with 52% achieving complete response and 22% partial response.

The treatment demonstrated modest toxicity, with no severe grade 3 or 4 side effects in over half of the patients, suggesting that methotrexate could be a safer alternative compared to more toxic therapies for this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of primary CNS lymphoma with methotrexate and deferred radiotherapy: a report of NABTT 96-07. Batchelor, T., Carson, K., O'Neill, A., et al.[2022]

In a phase II trial involving 36 patients with recurrent primary brain lymphomas, temozolomide showed a response rate of 31%, with nine complete and two partial responses, indicating its potential effectiveness as a treatment option.

The treatment was well-tolerated with negligible toxicity, and the one-year survival rate was 31%, suggesting that temozolomide could be a promising candidate for further evaluation, possibly in combination with methotrexate.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide as salvage treatment in primary brain lymphomas. Reni, M., Zaja, F., Mason, W., et al.[2022]

In a study of 56 rheumatoid arthritis patients, low-dose mizoribine (MZR) combined with methotrexate (MTX) significantly improved disease activity within three months, as measured by various indices.

No adverse effects were reported during the 12-month observation period, suggesting that low-dose MZR is a safe and effective option for patients who do not respond adequately to other treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mizoribine Synchronized Methotrexate Therapy should be Considered when Treating Rheumatoid Arthritis Patients with an Inadequate Response to Various Combination Therapies. Ikeda, K., Watanabe, K., Hirai, T., et al.[2018]

Tofacitinib 10 mg combined with methotrexate (MTX) and baricitinib 4 mg combined with MTX were found to be the most effective treatments for rheumatoid arthritis (RA) patients who did not respond adequately to previous therapies, based on a meta-analysis of 12 randomized controlled trials involving 5883 patients.

Both tofacitinib and baricitinib did not show a significant increase in the risk of serious adverse events compared to other treatments, indicating they are safe options for managing RA in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of the efficacy and safety of tofacitinib and baricitinib in patients with active rheumatoid arthritis: a Bayesian network meta-analysis of randomized controlled trials. Bae, SC., Lee, YH.[2021]

Patients with rheumatoid arthritis (RA) treated with disease-modifying agents (DMARDs) like azathioprine have a higher risk of developing certain cancers, with an overall standardized morbidity ratio (SMR) of 1.52, indicating a 52% increased risk compared to the general population.

Specifically, the risk for lymphoproliferative disorders and myeloma is significantly elevated, with an SMR of 8.05, and lung cancer also shows an increased risk (SMR of 3.37), highlighting the need for careful monitoring in this patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Occurrence of neoplasia in patients with rheumatoid arthritis enrolled in a DMARD Registry. Rheumatoid Arthritis Azathioprine Registry Steering Committee. Matteson, EL., Hickey, AR., Maguire, L., et al.[2013]

In a study of 57 patients treated with high-dose methotrexate-based chemotherapy, the overall median survival was 51 months, with particularly favorable outcomes for patients younger than 60, where 74% were alive at last follow-up.

Seventeen patients experienced treatment-related neurotoxicity, mostly among those who received whole brain radiotherapy, suggesting that for older patients, it may be safer to avoid this treatment to reduce neurotoxic risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term follow-up of high-dose methotrexate-based therapy with and without whole brain irradiation for newly diagnosed primary CNS lymphoma. Gavrilovic, IT., Hormigo, A., Yahalom, J., et al.[2022]

Abatacept treatment in 14 patients with rheumatoid arthritis led to significant changes in gene expression in synovial tissue, with 304 transcripts being modulated, particularly those related to immune processes.

The study found that the effects of abatacept and other DMARDs (like tocilizumab and methotrexate) converge on similar immune pathways, suggesting that these medications may share common mechanisms of action despite targeting different aspects of the immune response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Common Transcriptomic Effects of Abatacept and Other DMARDs on Rheumatoid Arthritis Synovial Tissue. Triaille, C., Durez, P., Sokolova, T., et al.[2022]

Methotrexate (MTX) has been identified as an effective sensitizer for both acquired and intrinsic resistance in metastatic melanoma (MM) cells to BRAF inhibitors (BRAFi's) like dabrafenib and encorafenib, potentially improving treatment outcomes.

The study found that combining MTX with dabrafenib leads to cell cycle arrest and apoptosis in resistant MM cells, with RAS codon 12 mutations serving as potential markers for predicting treatment efficacy, suggesting a new strategy to enhance survival rates in MM patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Methotrexate sensitizes drug-resistant metastatic melanoma cells to BRAF V600E inhibitors dabrafenib and encorafenib. Ross, KC., Chin, KF., Kim, D., et al.[2022]

The MR-CHOP therapy, which combines high-dose methotrexate with the R-CHOP regimen, showed a remarkable overall response rate of 100% in a pilot study of seven patients with primary central nervous system lymphoma, with 85.7% achieving complete remission.

While the treatment caused significant hematological toxicities, such as grade 4 leukocytopenia and neutropenia in some patients, these were transient and well-tolerated, suggesting that MR-CHOP could be a promising option for inducing remission despite the small sample size and short follow-up period.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-dose methotrexate with R-CHOP therapy for the treatment of patients with primary central nervous system lymphoma. Masaki, Y., Miki, M., Sun, Y., et al.[2022]

Citations

1.

clinicaltrials.gov

clinicaltrials.gov/study/NCT06466798

Study Details | NCT06466798 | Fourth Ventricular ...

The goal of this clinical trial is to assess the safety, toxicity, and antitumor activity of fourth ventricular infusions of nivolumab plus 5-azacytidine ...

2.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC12106150/

Individualized therapeutic approaches for relapsed and ...

This retrospective study aims to show a real-life single-center experience with clinical management of relapsed pediatric ependymomas

3.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC11816256/

Advances in the Repurposing and Blood–Brain Barrier ...

Both oral and IV irinotecan have demonstrated improved survival in patients with recurrent brain tumors when used in combination with other ...

4.

clinicaltrials.gov

clinicaltrials.gov/study/NCT06896110

NCT06896110 | Intrathecal Azacitidine and Nivolumab in ...

This is a single-arm open-label phase 1 dose escalation/expansion trial assessing the safety and efficacy of concurrent intrathecal azacitidine and intrathecal ...

5.

withpower.com

withpower.com/trial/phase-1-glioblastoma-4-2025-94423

Azacitidine + Nivolumab for Brain Cancer

Research shows that Nivolumab, part of the drug combination, has shown some effectiveness in treating brain metastases (cancer spread to the brain) in patients ...

6.

clinicaltrials.gov

clinicaltrials.gov/study/NCT06466798

Study Details | NCT06466798 | Fourth Ventricular ...

The goal of this clinical trial is to assess the safety, toxicity, and antitumor activity of fourth ventricular infusions of nivolumab plus 5-azacytidine ...

7.

braintumor.org

braintumor.org/news/new-brain-tumor-clinical-trials-april-october-2024/

New Brain Tumor Clinical Trials: April – October 2024

The goal of this phase I clinical trial is to assess the safety, toxicity, and antitumor activity of fourth ventricular infusions of nivolumab ...

8.

centerwatch.com

centerwatch.com/clinical-trials/listings/NCT06466798/fourth-ventricular-administration-of-immune-checkpoint-inhibitor-nivolumab-and-methotrexate-or-5-azacytidine-for-recurrent-medulloblastoma-ependymoma-and-other-cns-malignancies

Fourth Ventricular Administration of Immune Checkpoint ...

The goal of this clinical trial is to assess the safety, toxicity, and antitumor activity of fourth ventricular infusions of nivolumab plus ...