Intrathecal Azacitidine and Nivolumab for the Treatment of Patients with Recurrent High-Grade Glioma

Inclusion Criteria

• For patients age ≥ 18: Able and willing to provide written informed consent
• For patients aged 13-17: Parent/guardian of adolescent patient must have the ability to provide written informed consent. Adolescent patients must have the ability to provide written informed assent
• Stated willingness to comply with all trial procedures and availability for the duration of the trial
• Histologically confirmed diagnosis of World Health Organization grade IV high-grade glioma. Eligible diagnoses include: glioblastoma (IDH-wildtype), gliosarcoma, diffuse midline glioma (H3 K27-altered), diffuse hemispheric glioma (H3 G34-mutant), diffuse pediatric-type high-grade glioma (H3 and IDH-wildtype), astrocytoma IDH-mutant (grade 4)
• Previous first-line treatment with at least radiotherapy (and temozolomide in the case of glioblastoma or astrocytoma IDH-mutant [grade 4])
• Documented recurrence by diagnostic biopsy or contrast-enhanced magnetic resonance imaging (MRI) per Response Assessment in Neuro-Oncology Criteria (RANO) 2.0 criteria
• At least one measurable lesion per RANO 2.0 meeting the following criteria: Contrast enhancing or non-enhancing lesions with clearly defined margins by MRI scan, with both perpendicular diameters on a single slice of at least 10 mm, visible on two or more slices that are preferably, at most, 3 mm apart with 0-mm interslice gap
• Age ≥ 13
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 (age ≥ 16) or Lansky of ≥ 60 (age < 16)
• Disease status confirmed with baseline imaging performed within 28 days of day 1 of trial treatment. Patients with extracranial metastatic or leptomeningeal disease will be excluded
• Subjects must be on a stable or decreasing dose of corticosteroids for at least 7 days before enrollment
• Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L
• Hemoglobin ≥ 9.0 g/dL
• Platelets ≥ 75 x 10^9/L
• Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) ≤ 1.5 X upper limit of normal (ULN)
• Total bilirubin ≤ 1.5 X ULN (except subjects with known Gilbert syndrome, who can have total bilirubin < 3.0 mg/dL)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 X ULN
• Creatinine ≤ 2 X ULN OR calculated creatinine clearance ≥ 50 mL/min OR 24-hour urine creatinine clearance ≥ 50 ml/min
• Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test within 24 hours of starting therapy
• WOCBP must agree to follow instructions for methods of contraception
• Men who are sexually active with WOCBP must agree to follow instructions for methods of contraception
• Investigators will counsel WOCBP and male subjects who are sexually active with WOCBP on the importance of pregnancy prevention and implications of an unexpected pregnancy. At a minimum subjects must agree to the use of two methods of contraception, with one method being highly effective and the other method being either highly effective or less effective: starting at ICF or first dose and continuing 6 months after last dose of trial treatment: * Highly effective methods of contraception ** Male condoms with spermicide ** Hormonal methods including combined oral contraceptive pills, vaginal ring, injectables, implants, and intrauterine devices (IUD) ** Non-hormonal IUD ** Tubal ligation ** Vasectomy ** Complete Abstinence * Less effective methods of contraception ** Diaphragm with spermicide ** Cervical cap with spermicide ** Vaginal sponge ** Male condom without spermicide ** Progestin only pills ** Female condom
• An interval of ≥ 2 weeks from major surgery
• An interval of ≥ 4 weeks from chemotherapy, radiotherapy, or other investigational agents

Exclusion Criteria

• Presence of extracranial metastatic or leptomeningeal disease
• Patients with diffuse intrinsic pontine glioma, defined as tumors with a pontine epicenter and diffuse involvement of the pons
• Patients must not have active autoimmune disease that has required systemic treatment in the past 2 years (e.g. use of disease modifying agents, corticosteroids, or immunosuppressive drugs)
• Prior azacitidine for the treatment of cancer (prior administration of nivolumab or other immune checkpoint inhibitor is allowed)
• Subjects with major medical, neurologic, or psychiatric condition who are judged to be unable to fully comply with trial therapy or assessments
• Positive test for hepatitis B or C virus indicating acute or chronic infection, given the risk of reactivation with checkpoint inhibition
• Known history of testing positive for HIV or known acquired immunodeficiency syndrome (AIDS), due to the unknown effects of HIV on the immune response to intrathecal azacitidine and nivolumab
• Patients with a history of pneumonitis
• Evidence of active infection requiring treatment with intravenous (IV) antibiotics ≤ 7 days prior to initiation of trial therapy
• History of allergy to trial drug components
• Prisoners or subjects involuntarily incarcerated