10 Participants Needed

Nivolumab + Methotrexate/5-Azacytidine for Recurrent Brain Tumors

DI
PH
Bing Yu, PhD, FAHA appointed as the new ...
Overseen ByBangning Yu, MD, PhD
Age: Any Age
Sex: Any
Trial Phase: Phase 1
Sponsor: David Ilan Sandberg
No Placebo GroupAll trial participants will receive the active study treatment (no placebo)

Trial Summary

What is the purpose of this trial?

The goal of this clinical trial is to assess the safety, toxicity, and antitumor activity of fourth ventricular infusions of nivolumab plus 5-azacytidine for recurrent ependymoma and nivolumab plus methotrexate for recurrent medulloblastoma and other CNS malignancies. Additionally, the study will explore immunologic responses to nivolumab. The hypothesis is that local administration of nivolumab, an immune checkpoint inhibitor, is safe and will lead to even more robust treatment responses when administered following 5-azacytidine in patients with recurrent ependymoma or methotrexate in patients with medulloblastoma or other CNS tumors.

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.

What evidence supports the effectiveness of the drugs Nivolumab, Methotrexate, and 5-Azacytidine for treating recurrent brain tumors?

Methotrexate has shown effectiveness in extending survival in patients with primary brain lymphomas, and it has been used in combination with other drugs to treat central nervous system lymphomas. Additionally, Methotrexate has been found to sensitize drug-resistant cancer cells to other treatments, potentially enhancing their effectiveness.12345

Is there any safety information about Methotrexate for humans?

Methotrexate has been used in combination with other drugs for treating rheumatoid arthritis, and in one study, no patients experienced any adverse effects when it was used with low-dose mizoribine. However, patients with rheumatoid arthritis using disease-modifying drugs like Methotrexate may have an increased risk of certain cancers, particularly lymphoproliferative disorders.678910

How is the drug combination of Nivolumab, Methotrexate, and 5-Azacytidine unique for treating recurrent brain tumors?

This drug combination is unique because it combines Nivolumab, an immunotherapy that helps the immune system attack cancer cells, with Methotrexate and 5-Azacytidine, which are chemotherapy drugs that work by stopping cancer cell growth. This approach is novel as it integrates both immune system activation and direct cancer cell inhibition, potentially offering a new strategy for treating recurrent brain tumors where standard treatments are limited.3451112

Research Team

PH

Peter H. Yang, MD

Principal Investigator

The University of Texas Health Science Center, Houston

Eligibility Criteria

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.
See 13 more

Exclusion Criteria

Pregnant or lactating women
Enrolled in another treatment protocol
Evidence of untreated infection
See 2 more

Timeline

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

Treatment Details

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.
Participant Groups
2Treatment groups
Experimental Treatment
Group I: Nivolumab plus MethotrexateExperimental Treatment2 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-AzacytidineExperimental Treatment2 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)

Find a Clinic Near You

Who Is Running the Clinical Trial?

David Ilan Sandberg

Lead Sponsor

Trials
1
Recruited
10+

Peter H. Yang

Lead Sponsor

Trials
1
Recruited
10+

Findings from Research

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

References

Methotrexate sensitizes drug-resistant metastatic melanoma cells to BRAF V600E inhibitors dabrafenib and encorafenib. [2022]
High-dose methotrexate with R-CHOP therapy for the treatment of patients with primary central nervous system lymphoma. [2022]
Combination intrathecal therapy for meningeal leukemia: two versus three drugs. [2021]
Temozolomide as salvage treatment in primary brain lymphomas. [2022]
Immunochemotherapy with rituximab and temozolomide for central nervous system lymphomas. [2018]
Mizoribine Synchronized Methotrexate Therapy should be Considered when Treating Rheumatoid Arthritis Patients with an Inadequate Response to Various Combination Therapies. [2018]
Malignancies in the rheumatoid arthritis abatacept clinical development programme: an epidemiological assessment. [2022]
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. [2021]
Occurrence of neoplasia in patients with rheumatoid arthritis enrolled in a DMARD Registry. Rheumatoid Arthritis Azathioprine Registry Steering Committee. [2013]
Common Transcriptomic Effects of Abatacept and Other DMARDs on Rheumatoid Arthritis Synovial Tissue. [2022]
11.United Statespubmed.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. [2022]
12.United Statespubmed.ncbi.nlm.nih.gov
Treatment of primary CNS lymphoma with methotrexate and deferred radiotherapy: a report of NABTT 96-07. [2022]