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

Inclusion Criteria:

• Age 1 - 80 years at time of recurrence or progression

• Minimum body weight of 10 kilograms

• Diagnosis: Patients with histologically verified medulloblastoma, ependymoma, withrecurrence or progression anywhere in the brain and/or spine. Patients are alsoeligible if they have refractory disease, which will be defined as residual tumorwhich has not been completely cleared despite prior treatments. To be eligible,patients' disease must have originated or recurred in the posterior fossa of thebrain. Patients with central nervous system (CNS) malignancies besidesmedulloblastoma and ependymoma are also eligible if they have recurrent orrefractory disease in the posterior fossa

• Patient must have either measurable or evaluable tumor as assessed by magneticresonance imaging (MRI) of the brain and total spine. If the patient does not havemeasurable or evaluable tumor after surgery for resection and catheter placement,infusions will be held until there is measurable or evaluable tumor on subsequentMRI scans. Patients with no measurable or evaluable disease after surgical resectioncannot receive other systemic or intraventricular therapies and remain on study. Ifpatients or their guardians choose to pursue additional systemic or intraventriculartherapies during this time, the patients will be removed from the study. If patientsdo not receive additional systemic or intraventricular therapies and the ismeasurable or evaluable disease on subsequent imaging studies, then infusions mayproceed according to the study protocol.

• An implanted catheter in the fourth ventricle or posterior fossa tumor cavityattached to a ventricular access device or agreement to have one placed.

• Patients must have received their last dose of known myelosuppressive anticancertherapy at least 21 days prior to enrollment or at least 42 days if nitrosourea

• For patients receiving biologic or investigational agents (anti-neoplastic), thelast dose must have been received at least 7 days prior to study enrollment. Foragents 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 tooccur

• For patients receiving monoclonal antibody treatment and agents with prolongedhalf-lives, the last dose of the agent must have been received at least 28 daysprior to study enrollment

• For patients receiving Immune Effector Cell (IEC) Therapy (e.g., Chimeric antigenreceptor (CAR) T-cells), viral therapy, or cellular therapy, patients must havereceived therapy ≥ 3 months prior to study enrollment. Patients who have receivedallogeneic stem cell transplants must wait at least 6 months prior to enrollmentwith no evidence of active graft versus host disease. Patients who have receivedautologous stem cell transplants must wait at least 3 months since transplant toenroll.

• Patients must have received their last fraction of standard upfront radiation ≥ 3months 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 orgreater if > 16 years of age

• Patients must have recovered from the acute toxic effects of all prior anticancerchemotherapy

• Patients must have adequate organ and marrow function as defined below:

• Absolute neutrophil count > 1.0 x 10^9 cells/L

• Platelets > 50 x 10^9 cells/L (unsupported, defined as no platelet transfusionwithin 7 days)

• Hemoglobin ≥ 8 g/dL (may receive transfusions)

• Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN)

• prothrombin time test with an international normalized ratio (PT/INR), partialthromboplastin time (PTT) ≤ 1.5 x ULN

• Alanine aminotransferase (ALT) [serum glutamic-pyruvic transaminase (SGPT)] andaspartate aminotransferase (AST) [serum glutamic-oxaloacetic transaminase (SGOT)] < 3 x institutional upper limit of normal (ULN)

• Albumin ≥ 3 g/dL

• Normal creatinine level for age according to hospital or outside lab standards. Ifcreatinine is outside normal range, then Chronic kidney disease (CKD)-epicalculation will be performed for patients age >25. Patients age > 25 with estimatedglomerular filtration rate (eGFR) > 60 ml/min/1.73m2 will be eligible and patientswho do not meet this standard require nephrologist consultation to determine safetyof enrollment. For patients ages 1 to 25 with creatinine outside normal range,Chronic kidney disease (CKD)--U25 calculation will be performed. Patients ages 1 to 25 with eGFR > 40 ml/min/1.73m2 will be eligible and patients who do not meet thisstandard require nephrologist consultation to determine safety of enrollment.

• Patient or patient's legal representative, parent(s), or guardian able to providewritten informed consent.

• Patients of childbearing age and their parents will be informed that pregnancy is anexclusion criterion for the study. Male patients will be informed to use condoms ifsexually active. Female patients will be advised to use contraceptives to preventpregnancy if sexually active including male or female condoms, oral contraceptives,contraceptive injections, or other forms of contraception advised by primary carephysician or obstetrician/gynecologist

Exclusion Criteria:

• Enrolled in another treatment protocol

• Patient is currently receiving corticosteroids that cannot be weaned off at leastone week prior to first Nivolumab infusion

• Evidence of untreated infection

• Pregnant or lactating women

• Patient that has had allogenic stem cell transplant