Stereotactic Radiosurgery, Nivolumab, and Valproic Acid in Treating Patients with Recurrent Glioblastoma

Inclusion Criteria

• Willingness and ability to provide written informed consent and to comply with the study protocol as judged by the investigator
• Histologically confirmed diagnosis of World Health Organization grade IV malignant glioma (glioblastoma or gliosarcoma)
• Recurrence of glioblastoma (GBM) since completion of most recent therapy; recurrence must be documented by diagnostic biopsy or contrast enhanced magnetic resonance imaging (MRI) performed within 21 days prior to entering the study per Response Assessment in Neuro-Oncology (RANO) criteria
• At least one measurable GBM lesion that meets the following criteria: * Contrast enhancing and clearly defined, bi-dimensionally measurable margins, and * At least two perpendicular diameters measuring >= 10 mm and no diameters measuring >= 35 mm * (Note: MRI measurements will not include surgical cavity, cyst, or necrotic area)
• Karnofsky performance status >= 70%
• Subject must have a life expectancy >= 12 weeks
• Absolute neutrophil count (ANC) >= 1,500 /mcL
• White blood cell count (WBC) >= 2,000 /mcL
• Platelets >= 100,000/mcL
• Hemoglobin >= 9 g/dL or >= 5.6 mmol/L
• Serum creatinine =< 1.5 X upper limit of normal (institutional upper limit of normal, IULN) OR measured or calculated creatinine clearance (GFR can also be used in place of creatinine or creatinine clearance [CrCl]) >= 60 mL/min for subject with creatinine levels > 1.5 X institutional ULN
• Serum total bilirubin =< 1.5 mg/dL
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 X IULN
• Prothrombin time (PT) and activated partial thromboplastin time (aPTT) =< 1.5 X IULN, AND international normalized ratio (INR) =< 1.5 X IULN (unless subject is receiving anticoagulant therapy, as long as PT or PTT is within therapeutic range of intended use of anticoagulants)
• Triiodothyronine measurement (T3), thyroxine (T4) or thyroid-stimulating hormone (TSH) =< 3.0 x IULN
• Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within 24 hours prior to receiving nivolumab; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
• Women of childbearing potential and men must agree to use adequate contraception prior to study entry and for the duration described below * WOCBP must use agree to use contraception until 5 half-lives plus 30 days following last study intervention (23 weeks after last dose of nivolumab) * Male subjects who are sexually active with WOCBP must agree to use adequate contraception until 5 half-lives plus 90 days following last study intervention (31 weeks after last dose of nivolumab)

Exclusion Criteria

• Presence of extracranial metastatic or leptomeningeal disease
• Known additional malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, indolent prostate cancer or chronic lymphocytic leukemia, or in situ cervical cancer that has undergone potentially curative therapy
• Subject is unable or unwilling to discontinue use of prohibited medications
• Subject is unable or unwilling to participate in a study related procedure
• Subject is a prisoner
• Subject has received any of the following: * Chemotherapy, biological therapy, or surgery within 4 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks prior to on-study date * Radiation therapy, within 10 weeks prior to entering the study or those who have not recovered from adverse events due to radiation administered more than 10 weeks prior to on-study date * Prior therapy with bevacizumab * Prior therapy with an anti-programed cell death 1 (PD-1), anti-programed cell death 1-ligand (PD-L)1, anti-PD-L2, anti-cluster of differentiation (CD)137, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody * Prior treatment with an HDAC inhibitor, with the exception of prior or current treatment with valproate * Any investigational agents or have had any investigational agent within the 30 days prior to on-study date * A live vaccine within 30 days prior to on-study date * Previous treatment with carmustine wafer except when administered as first line treatment and at least 6 months prior to on-study date
• Subject requires escalating or chronic supraphysiologic doses of corticosteroids > 2 mg dexamethasone or equivalent
• Active infection requiring systemic therapy
• Subject has history of severe infusion reactions related to prior biologics or antibody-based treatments
• Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies), active hepatitis B or hepatitis C
• An active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires immunosuppressive agents; subjects with any of the following conditions are eligible for the study: vitiligo or resolved childhood asthma/atopy, type I diabetes mellitus, conditions requiring intermittent use of bronchodilators or local steroid injections, hypothyroidism stable on hormone replacement, Sjorgen’s syndrome, or psoriasis not requiring chronic and systemic immunosuppressive treatment
• Evidence of interstitial lung disease or active, non-infectious pneumonitis
• Evidence of > grade 1 central nervous system (CNS) hemorrhage or > grade 3 venous thromboembolism
• History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
• History of clinically significant liver disease, urea cycle disorder, or genetic liver problem caused by a mitochondrial disorder (e.g., Alpers-Huttenlocher syndrome)
• Significant history of uncontrolled cardiac disease including uncontrolled hypertension, unstable angina, cerebrovascular accidents or myocardial infarction within the last 6 months, and New York Heart Association (NYHA) grade II or greater congestive heart failure (CHF), or serious cardiac arrhythmia uncontrolled by medication
• History of central nervous system disease (e.g., seizures) unrelated to cancer unless adequately controlled by medication
• History of pulmonary hemorrhage/hemoptysis >= grade 2 (defined as >= 2.5 mL bright red blood per episode) within 1 month prior to on-study date
• History or evidence of inherited bleeding diathesis or significant coagulopathy at risk of bleeding (i.e., in the absence of therapeutic anticoagulation); current or recent (within 10 days of study enrollment) use of anticoagulants that, in the opinion of the investigator, would place the subject at significant risk for bleeding; prophylactic use of anticoagulants is allowed
• Surgical procedure (including open biopsy, surgical resection, wound revision, or any other major surgery involving entry into a body cavity) or significant traumatic injury within 28 days prior to on-study date, or anticipation of need for major surgical procedure during the course of the study
• Subjects unable (due to existent medical condition, e.g., pacemaker or implantable cardioverter-defibrillator [ICD] device) or unwilling to have a head contrast enhanced MRI