Panobinostat and Stereotactic Radiation Therapy in Treating Patients With Brain Tumors

Inclusion Criteria:

1. Patient age is \> or = 18 years
2. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status of \< or = 2
3. Ability to provide written informed consent obtained prior to participation in the study and any related procedures being performed
4. Patients must meet the following laboratory criteria:

   * Hematology:

     * Neutrophil count of \> 1500/mm3
     * Platelet count of \> 100,000/mm3L
     * Hemoglobin \> or = 9 g/dL
   * Biochemistry:

     * AST/SGOT and ALT/SGPT \< or = 2.5 x upper limit of normal (ULN) or \< or = 5.0 x ULN if the transaminase elevation is due to disease involvement
   * Serum bilirubin \< or = 1.5 x ULN
   * Serum creatinine \< or = 1.5 x ULN or 24-hour creatinine clearance \> or = 50 ml/min
   * Total serum calcium (corrected for serum albumin) or ionized calcium \> or = LLN
   * Serum potassium \> or = LLN
   * Serum sodium \> or = LLN
   * Serum albumin \> or = LLN or 3g/dl
   * Patients with any elevated Alkaline Phosphatase due to bone metastasis can be enrolled
5. Clinically euthyroid. Note: Patients are permitted to receive thyroid hormone supplements to treat underlying hypothyroidism.
6. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within 7 days of the first administration of study treatment. and must be willing to use two methods of contraception one of them being a barrier method during the study and for 3 months after last study drug administration
7. Pathologic diagnosis and other conditions relating to the different arms of the study:

   * Arm A Recurrent glioma: Pathological diagnosis of glioma (grade 2-4) is required. All patients are required to have initially undergone fractionated radiation therapy, to between 55 Gy to 70 Gy in fractions of 1.8-2 Gy as part of 'first line therapy'. The diagnosis of 'recurrence' is to be made by the treating physician on the basis of radiological and clinical data. Measurable disease is not required.
   * Arm A High-grade meningioma: Pathological diagnosis of high-grade meningioma, as defined by WHO grade 2 or 3 (also known as atypical and anaplastic/malignant meningioma). WHO grade 1 meningiomas with an elevated Ki67 proliferation rate of \> or = 8% are also considered high-grade for the purposes of this trial, due to their poor prognosis32, 86-88. The meningioma may be treated in the scenario of either adjuvant treatment (radiation therapy following complete / sub-total / biopsy only resection) or recurrent disease (re-growth following surgery alone). Measurable disease is not required.
   * Arm B Large brain metastases: Pathological diagnosis of malignancy is required, from either the primary tumor or a metastasis. A radiological diagnosis (CT or MRI scan) of one of more brain metastases is required. At least one of the brain metastases to be treated as part of this study must be 2.5cm or larger in maximal diameter. The brain metastasis/es to be treated may not be more than 4cm in maximal diameter, as assessed by CT or MRI scan. The brain metastasis may either be un-resected or partially resected, provided that the target lesion (which may include a resection cavity) remains between 2.5 and 4cm in diameter, as defined in section 6. Whole brain radiation therapy may or may-not have been delivered prior to entering this protocol.

Exclusion Criteria:

1. Prior HDAC, DAC, HSP90 inhibitors or valproic acid for the treatment of cancer
2. Patients who will need valproic acid for any medical condition during the study or within 5 days prior to first panobinostat treatment
3. Impaired cardiac function including any one of the following:

   * History or presence of sustained ventricular tachyarrhythmia.
   * Any history of ventricular fibrillation or torsade de pointes
   * Bradycardia defined as HR \< 50 bpm. Patients with pacemakers are eligible if HR \> or = 50 bpm.
   * Screening ECG with a QTc \> 450 msec
   * Right bundle branch block + left anterior hemiblock (bifascicular block)
   * Patients with myocardial infarction or unstable angina \< or = 6 months prior to starting study drug
   * Other clinically significant heart disease (e.g., CHF NY Heart Association class III or IV , uncontrolled hypertension, history of labile hypertension, or history of poor compliance with an antihypertensive regimen)
4. Uncontrolled hypertension
5. Concomitant use of drugs with a risk of causing torsades de pointes
6. Patients with unresolved diarrhea \> or = grade 2
7. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral panobinostat (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, obstruction, or stomach and/or small bowel resection)
8. Other concurrent severe and/or uncontrolled medical conditions
9. Patients who have received chemotherapy, any investigational drug or undergone major surgery \< 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy.
10. Women who are pregnant or breast feeding or women of childbearing potential (WOCBP) not willing to use a double barrier method of contraception during the study and 3 months after the end of treatment. One of these methods of contraception must be a barrier method. WOCBP are defined as sexually mature women who have not undergone a hysterectomy or who have not been naturally postmenopausal for at least 12 consecutive months (i.e., who has had menses any time in the preceding 12 consecutive months). Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within 7 days of the first administration of oral panobinostat.
11. Male patients whose sexual partners are WOCBP not using a double method of contraception during the study and 3 months after the end of treatment. One of these methods must be a condom
12. Patients with a history of another primary malignancy within 5 years other than curatively treated CIS of the cervix, or basal or squamous cell carcinoma of the skin
13. Patients with known positivity for human immunodeficiency virus (HIV) or hepatitis C; baseline testing for HIV and hepatitis C is not required
14. Patients with any significant history of non-compliance to medical regimens or with inability to grant a reliable informed consent
15. Allergy to MRI contrast agent.
16. Any anti-cancer treatment within 2 weeks of initiating treatment as part of this trial, including cytotoxic chemotherapy (e.g. temozolomide), radiation therapy (single fraction or fractionated), and biological therapies (e.g. mono-clonal antibodies, tyrosine kinase inhibitors, interferon). Hormonal therapies (e.g. in breast and prostate cancer) are allowed both prior to and during treatment.
17. Exclusion criteria specific to arms of the trial:

    * Arm A Recurrent glioma: The subject has received more than one prior course of radiation therapy within the target volume to be treated as part of this protocol. Additional courses of radiation therapy (single fraction or fractionated) are permitted if outside of the volume to be treated.
    * Arm A High-grade meningioma: The subject has received a prior course of radiation therapy within the target volume to be treated as part of this protocol.
    * Arm B Large brain metastases: The subject has received a prior course of radiation therapy within the target volume to be treated as part of this protocol, aside from whole brain radiation.