Trial of Panobinostat in Children With Diffuse Intrinsic Pontine Glioma

STRATUM 1 - INCLUSION CRITERIA * DIAGNOSIS - Patients with progressive DIPG or H3K27M+ Thalamic DMG , as defined by progressive neurologic abnormalities or worsening neurologic status not explained by causes unrelated to tumor progression (e.g., anticonvulsant or corticosteroid toxicity wean, electrolyte disturbances, sepsis, hyperglycemia, etc.), OR an increase in the bi-dimensional measurement, taking as a reference the smallest disease measurement recorded since diagnosis, OR the appearance of a new tumor lesion since diagnosis. * Please note: patients with a radiographically typical DIPG, defined as a tumor with a pontine epicenter and diffuse involvement of more than 2/3 of the pons, are eligible without histologic confirmation. * Patients with pontine lesions that do not meet these radiographic criteria will be eligible if there is histologic confirmation of malignant glioma WHO II-IV. * Thalamic Diffuse Midline Glioma patients will be eligible if there is tissue confirmation of the H3K27M mutation by immunohistochemistry or by gene testing performed in a CLIA certified laboratory of the investigator's choice. * AGE - Patients must be ≥ 2 but \< 22 years of age at the time of enrollment. * BSA * Patients must have a BSA ≥ 0.80 m2 for dose 5mg/m2. * Patients must have a BSA ≥ 0.65 m2 for doses of 10mg/m2 - 22 mg/m2. * Patients must have a BSA ≥ 0.50 m2 for doses of 28 mg/m2 - 36 mg/m2. * ABILITY TO SWALLOW - Patient must be able to swallow capsules whole. * PERFORMANCE STATUS - Karnofsky Performance Scale (KPS for \> 16 years of age) or Lansky Performance Score (LPS for ≤ 16 years of age) assessed within 7 days of enrollment must be ≥ 50%. Patients who are unable to walk because of neurologic deficits, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score. * PRIOR THERAPY - Patients must have received a minimum of 54 Gy focal irradiation administered over approximately 42 days prior to enrollment. Patients must have recovered from the acute treatment-related toxicities (defined as \< grade 1) of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study. * MYELOSUPPRESSIVE CHEMOTHERAPY - Patients must have received their last dose of known myelosuppressive anticancer therapy or immunotherapy at least 21 days prior to enrollment (42 days if prior nitrosourea). * INVESTIGATIONAL/ BIOLOGIC AGENT: * Biologic or investigational agent (anti-neoplastic): Patient must have recovered from any acute toxicity potentially related to the agent and received their last dose of the investigational or biologic agent ≥ 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 adverse events are known to occur, and discussed with the principal investigator.) * Monoclonal antibody treatment and agents with known prolonged half-lives: At least three half-lives must have elapsed prior to enrollment. (Note: A list of the half-lives of commonly used monoclonal antibodies is available on the PBTC webpage under Generic Forms and Templates.) * RADIATION THERAPY - Patients must have had their last fraction of: * Craniospinal irradiation or radiation to ≥ 50% of pelvis \> 3 months prior to enrollment. * Focal irradiation to the primary site \> 42 days prior to enrollment * Local palliative irradiation other than previously irradiated primary site (small port) ≥ 14 days * ORGAN FUNCTION - Patients must have adequate organ and marrow function as defined below: * Absolute neutrophil count ≥ 1,000/mm3 * Platelets ≥ 100,000/ mm3 (unsupported, defined as no platelet transfusion within 7 days, and recovery from post-transfusion nadir) * Hemoglobin ≥ 8 g/dl (may receive transfusions) * Total bilirubin ≤ 1.5 times institutional upper limit of normal (ULN) * ALT(SGPT) \< 3 x institutional upper limit of normal * Albumin ≥ 3 g/dl * Potassium ≥ LLN * Serum total calcium (correct for serum albumin) or ionized calcium ≥ LLN * Serum creatinine based on age/gender as noted below. Patients that do not meet the criteria below but have a 24-hour Creatinine Clearance or GFR (radioisotope or iothalamate) ≥ 70 ml/min/1.73 m2 are eligible. Maximum Serum Creatinine for age/gender: * Age 2 to \< 6 years: 0.8 mg/dL (male); 0.8 mg/dL (female) * Age 6 to \< 10 years: 1 mg/dL (male); 1 mg/dL (female) * Age 10 to \< 13 years: 1.2 mg/dL (male); 1.2 mg/dL (female) * Age 13 to \< 16 years: 1.5 mg/dL (male); 1.4 mg/dL (female) * Age ≥ 16 years: 1.7 mg/dL (male); 1.4 mg/dL (female) * Cardiac Function: * Left ventricular ejection fraction ≥ 50 by gated radionuclide study OR shortening fraction of ≥ 27% by echocardiogram * Patient has no ventricular arrhythmias except for benign premature ventricular contractions. * Patient has a QTc interval \< 450 ms. * GROWTH FACTORS - Patients must be off all colony-forming growth factor(s) for at least 7 days prior to enrollment (i.e. filgrastim, sargramostim or erythropoietin). 14 days must have elapsed if patients received PEG formulations. * FRUIT - Patients must agree to avoid grapefruit or grapefruit juice and Seville (sour) oranges during the entire study. * PREGNANCY STATUS - Female patients of childbearing potential must have a negative serum or urine pregnancy test. * PREGNANCY PREVENTION - Patients of childbearing or child fathering potential must be willing to use a medically acceptable form of birth control, which includes abstinence, while being treated on this study and for 3 months after the last dose of panobinostat. * INFORMED CONSENT - The patient or parent/guardian is able to understand the consent and is willing to sign a written informed consent document according to institutional guidelines. STRATUM 1 - EXCLUSION CRITERIA * PRIOR THERAPY * Patients who have had \> 60 Gy total radiation to the pons (e.g. patients who have received re-irradiation). * Patients have had prior HDAC, DAC, HSP90 inhibitors for the treatment of their DIPG. * Patients have had valproic acid within 28 days prior to enrollment. * Patients have had prior bone marrow transplant. * NEUROLOGICAL STATUS - Patients have significant acute deterioration in neurologic status in 72 hours prior to enrollment, in the opinion of the treating physician. * GASTROINTESTINAL * Patients have impairment of GI function or GI disease that may significantly alter the absorption of panobinostat; for example severe inflammatory bowel disease. * Patients have diarrhea \> CTCAE grade 2. * SYSTEMIC ILLNESS - Patients have any clinically significant unrelated systemic illness (serious infections or significant cardiac, pulmonary, hepatic or other organ dysfunction), that in the opinion of the investigator would compromise the ability of the patient to tolerate protocol therapy or put them at additional risk for toxicity or would interfere with the study procedures or results. * OTHER MALIGNANCY - Patients have a history of any other malignancy. * TRANSFUSIONS - Patients are known to be refractory to red blood cell or platelet transfusions. * CONCURRENT THERAPY * Patients who are receiving any other anticancer or investigational drug therapy * Patients who are required to receive any medication which can prolong the QTc interval. Please see Protocol Appendix B: Medications Which May Cause QTc Prolongation. * BREASTFEEDING - Female patient IS breastfeeding. * INABILITY TO PARTICIPATE - Patients who in the opinion of the investigator are unwilling or unable to return for required follow-up visits or obtain follow-up studies required to assess toxicity to therapy or to adhere to drug administration plan, other study procedures, and study restrictions STRATUM 2 - INCLUSION CRITERIA * DIAGNOSIS - Patients with DIPG who have not yet progressed by clinical or radiographic criteria. * Please note: patients with a radiographically typical DIPG, defined as a tumor with a pontine epicenter and diffuse involvement of more than 2/3 of the pons, are eligible without histologic confirmation. * Patients with pontine lesions that do not meet these radiographic criteria will be eligible if there is histologic confirmation of malignant glioma WHO II-IV. * AGE - Patients must be ≥ 2 but \< 22 years of age at the time of enrollment. * BSA Patients must have a BSA ≥ 0.80 m2 for dose 5mg/m2. Patients must have a BSA ≥ 0.65 m2 for doses of 10mg/m2 - 22 mg/m2. Patients must have a BSA ≥ 0.50 m2 for doses of 28 mg/m2 - 36 mg/m2. * ABILITY TO SWALLOW - Patient must be able to swallow capsules whole. * PERFORMANCE STATUS - Karnofsky Performance Scale (KPS for \> 16 years of age) or Lansky Performance Score (LPS for ≤ 16 years of age) assessed within 7 days of enrollment must be ≥ 50%. Patients who are unable to walk because of neurologic deficits, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score. * PRIOR THERAPY - Patients must have received a minimum of 54 Gy focal irradiation administered over approximately 42 days prior to enrollment. Patients must not have received any other prior therapy for treatment of their CNS malignancy besides standard radiation therapy. o Patients must have recovered from the acute treatment-related toxicities (defined as \< grade 1) of radiotherapy prior to entering this study. * RADIATION THERAPY - Patients must have had their last fraction of focal irradiation to the primary site \> 14 days prior to enrollment. Patients must not have received local palliative irradiation or craniospinal irradiation. * ORGAN FUNCTION - Patients must have adequate organ and marrow function as defined below: * Absolute neutrophil count ≥ 1,000/mm3 * Platelets ≥ 100,000/ mm3 (unsupported, defined as no platelet transfusion within 7 days, and recovery from post-transfusion nadir) * Hemoglobin ≥ 8 g/dl (may receive transfusions) * Total bilirubin ≤ 1.5 times institutional upper limit of normal (ULN) * ALT(SGPT) \< 3 x institutional upper limit of normal * Albumin ≥ 3 g/dl * Potassium ≥ LLN * Serum total calcium (correct for serum albumin) or ionized calcium ≥ LLN * Serum creatinine based on age/gender as noted below. Patients that do not meet the criteria in Table 9 but have a 24-hour Creatinine Clearance or GFR (radioisotope or iothalamate) ≥ 70 ml/min/1.73 m2 are eligible. * Age 2 to \< 6 years: 0.8 mg/dL (male); 0.8 mg/dL (female) * Age 6 to \< 10 years: 1 mg/dL (male); 1 mg/dL (female) * Age 10 to \< 13 years: 1.2 mg/dL (male); 1.2 mg/dL (female) * Age 13 to \< 16 years: 1.5 mg/dL (male); 1.4 mg/dL (female) * Age ≥ 16 years: 1.7 mg/dL (male); 1.4 mg/dL (female) * CARDIAC FUNCTION: * Left ventricular ejection fraction ≥ 50 by gated radionuclide study OR shortening fraction of ≥ 27% by echocardiogram * Patient has no ventricular arrhythmias except for benign premature ventricular contractions. * Patient has a QTc interval \< 450 ms. * GROWTH FACTORS - Patients must be off all colony-forming growth factor(s) for at least 7 days prior to enrollment (i.e. filgrastim, sargramostim or erythropoietin). 14 days must have elapsed if patients received PEG formulations. * FRUIT - Patients must agree to avoid grapefruit or grapefruit juice and Seville (sour) oranges during the entire study. * PREGNANCY STATUS - Female patients of childbearing potential must have a negative serum or urine pregnancy test. * PREGNANCY STATUS - Patients of childbearing or child fathering potential must be willing to use a medically acceptable form of birth control, which includes abstinence, while being treated on this study and for 3 months after the last dose of panobinostat. * INFORMED CONSENT - The patient or parent/guardian is able to understand the consent and is willing to sign a written informed consent document according to institutional guidelines. STRATUM 2 - EXCLUSION CRITERIA * PRIOR THERAPY - Patients who have had \> 60 Gy total radiation to the pons or thalamus (e.g. patients who have received re-irradiation) * NEUROLOGICAL STATUS - Patients have significant acute deterioration in neurologic status in 72 hours prior to enrollment, in the opinion of the treating physician. * GASTROINTESTINAL * Patients have impairment of GI function or GI disease that may significantly alter the absorption of panobinostat; for example severe inflammatory bowel disease. * Patients have diarrhea \> CTCAE grade 2. * SYSTEMIC ILLNESS - Patients have any clinically significant unrelated systemic illness (serious infections or significant cardiac, pulmonary, hepatic or other organ dysfunction), that in the opinion of the investigator would compromise the ability of the patient to tolerate protocol therapy or put them at additional risk for toxicity or would interfere with the study procedures or results. * OTHER MALIGNANCY - Patients have a history of any other malignancy. * TRANSFUSIONS - Patients are known to be refractory to red blood cell or platelet transfusions. * CONCURRENT THERAPY * Patients who are receiving any other anticancer or investigational drug therapy * Patients who are required to receive any medication which can prolong the QTc interval. Please see Appendix B: Medications Which May Cause QTc Prolongation. * BREASTFEEDING - Female patient is breastfeeding. * INABILITY TO PARTICIPATE - Patients who in the opinion of the investigator are unwilling or unable to return for required follow-up visits or obtain follow-up studies required to assess toxicity to therapy or to adhere to drug administration plan, other study procedures, and study restrictions