Fourth Ventricular Administration of Immune Checkpoint Inhibitor (Nivolumab) and Methotrexate or 5-Azacytidine for Recurrent Medulloblastoma, Ependymoma, and Other CNS Malignancies

NCT06466798 | Withdrawn Phase 1 DMC FDA Drug

• 1 other identifier: HSC-MS-24-0240
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

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.

Conditions

Recurrent Ependymoma; Recurrent Medulloblastoma; CNS Malignancies

Outcome Measures

Primary Outcomes (1)

• Safety as assessed by the number of participants with a new neurological toxicity that is graded as Grade 3 or higher and that is probably or definitely related to infusions [that is, classified as dose-limiting toxicity (DLT)]

  Adverse events will be graded according to the NCI common terminology criteria version 5.0. Adverse events not included in the Common Terminology Criteria for Adverse Events (CTCAE) chart will be graded as follows: * Grade 1: Mild: discomfort present with no disruption of daily activity, no treatment required beyond prophylaxis * Grade 2: Moderate: discomfort present with some disruption of daily activity, require treatment. * Grade 3: Severe: discomfort that interrupts normal daily activity, not responding to first line treatment. * Grade 4: Life Threatening: discomfort that represents immediate risk of death.

  from start of treatment to end of treatment (about 12 weeks)

Secondary Outcomes (1)

• Number of participants who responded to therapy as determined by MRI imaging

  baseline, within 7 days of completing final infusion (about 12 weeks)

Study Arms (2)

Nivolumab plus Methotrexate

EXPERIMENTAL

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.

Drug: Nivolumab; Drug: Methotrexate

Nivolumab plus 5-Azacytidine

EXPERIMENTAL

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.

Drug: Nivolumab; Drug: 5-Azacytidine

Interventions

Nivolumab DRUG

Nivolumab infusions will be given intraventricularly once every other week for 12 weeks. Dosing will be based upon patient body weight.

Nivolumab plus 5-Azacytidine; Nivolumab plus Methotrexate

Methotrexate DRUG

2 mg methotrexate infusions will be given intraventricularly daily for 4 consecutive days per week every other week for 12 weeks.

Nivolumab plus Methotrexate

5-Azacytidine DRUG

10 mg 5-Azacytidine infusions will be given intraventricularly once weekly for twelve consecutive weeks.

Nivolumab plus 5-Azacytidine

Eligibility Criteria

• Age: 1 Year - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 1 - 80 years at time of recurrence or progression
• Minimum body weight of 10 kilograms
• Diagnosis: Patients with histologically verified medulloblastoma, ependymoma, with recurrence or progression anywhere in the brain and/or spine. Patients are also eligible if they have refractory disease, which will be defined as residual tumor which has not been completely cleared despite prior treatments. To be eligible, patients' disease must have originated or recurred in the posterior fossa of the brain. Patients with central nervous system (CNS) malignancies besides medulloblastoma and ependymoma are also eligible if they have recurrent or refractory disease in the posterior fossa
• Patient must have either measurable or evaluable tumor as assessed by magnetic resonance imaging (MRI) of the brain and total spine. If the patient does not have measurable or evaluable tumor after surgery for resection and catheter placement, infusions will be held until there is measurable or evaluable tumor on subsequent MRI scans. Patients with no measurable or evaluable disease after surgical resection cannot receive other systemic or intraventricular therapies and remain on study. If patients or their guardians choose to pursue additional systemic or intraventricular therapies during this time, the patients will be removed from the study. If patients do not receive additional systemic or intraventricular therapies and the is measurable or evaluable disease on subsequent imaging studies, then infusions may proceed according to the study protocol.
• An implanted catheter in the fourth ventricle or posterior fossa tumor cavity attached to a ventricular access device or agreement to have one placed.
• Patients must have received their last dose of known myelosuppressive anticancer therapy at least 21 days prior to enrollment or at least 42 days if nitrosourea
• For patients receiving biologic or investigational agents (anti-neoplastic), the last dose must have been received at least 7 days prior to study enrollment. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which such events are known to occur
• For patients receiving monoclonal antibody treatment and agents with prolonged half-lives, the last dose of the agent must have been received at least 28 days prior to study enrollment
• For patients receiving Immune Effector Cell (IEC) Therapy (e.g., Chimeric antigen receptor (CAR) T-cells), viral therapy, or cellular therapy, patients must have received therapy ≥ 3 months prior to study enrollment. Patients who have received allogeneic stem cell transplants must wait at least 6 months prior to enrollment with no evidence of active graft versus host disease. Patients who have received autologous stem cell transplants must wait at least 3 months since transplant to enroll.
• Patients must have received their last fraction of standard upfront radiation ≥ 3 months prior to enrollment and ≥ 28 days for palliative radiation.
• Life expectancy of at least 12 weeks in the opinion of the principal investigator
• Lansky score of 50 or greater if ≤16 years of age or Karnofsky score of 50 or greater if \> 16 years of age
• Patients must have recovered from the acute toxic effects of all prior anticancer chemotherapy
• Patients must have adequate organ and marrow function as defined below:
• Absolute neutrophil count \> 1.0 x 10\^9 cells/L

You may not qualify if:

• Enrolled in another treatment protocol
• Patient is currently receiving corticosteroids that cannot be weaned off at least one week prior to first Nivolumab infusion
• Evidence of untreated infection
• Pregnant or lactating women
• Patient that has had allogenic stem cell transplant

Sponsors & Collaborators

• Jeffrey Treiber: lead

MeSH Terms

Conditions

Ependymoma; Medulloblastoma; Central Nervous System Neoplasms

Interventions

Nivolumab; Methotrexate; Azacitidine

Condition Hierarchy (Ancestors)

Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Neuroectodermal Tumors, Primitive; Nervous System Neoplasms; Neoplasms by Site; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Study Officials

• Jeffrey M. Treiber, MD

  The University of Texas Health Science Center, Houston

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: June 13, 2024
• First Posted: June 20, 2024
• Study Start: July 15, 2024
• Primary Completion (Estimated): July 1, 2027
• Study Completion (Estimated): July 1, 2027
• Last Updated: January 8, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share