Testing the Drug, Panobinostat, for Patients with Diffuse Intrinsic Pontine Glioma

Inclusion Criteria

• RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): Patients with progressive DIPG, 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 World Health Organization (WHO) II-IV
• RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): Body surface area (BSA) * Patients must have a BSA >= 0.80 m^2 for dose 5 mg/m^2 * Patients must have a BSA >= 0.65 m^2 for doses of 10 mg/m^2 - 22 mg/m^2 * Patients must have a BSA >= 0.50 m^2 for doses of 28 mg/m^2 - 36 mg/m^2
• RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): Patient must be able to swallow capsules whole
• RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): 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
• RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): 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
• RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): 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)
• RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): 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
• RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): 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 Pediatric Brain Tumor Consortium (PBTC) webpage under Generic Forms and Templates
• RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): 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
• RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): Absolute neutrophil count >= 1,000/mm^3
• RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): Platelets >= 100,000/mm^3 (unsupported, defined as no platelet transfusion within 7 days, and recovery from post-transfusion nadir)
• RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): Hemoglobin >= 8 g/dl (may receive transfusions)
• RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): Total bilirubin =< 1.5 times institutional upper limit of normal (ULN)
• RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional upper limit of normal
• RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): Albumin >= 3 g/dl
• RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): Potassium >= lower limit of normal (LLN)
• RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): Serum total calcium (correct for serum albumin) or ionized calcium >= LLN
• RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): 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 glomerular filtration rate (GFR) (radioisotope or iothalamate) >= 70 ml/min/1.73 m^2 are eligible * 2 to < 6 years: 0.8 mg/dL * 6 to < 10 years: 1 mg/dL * 10 to < 13 years: 1.2 mg/dL * 13 to < 16 years: 1.5 mg/dL (male), 1.4 mg/dL (female) * >= 16 years: 1.7 mg/dL (male), 1.4 mg/dL (female)
• RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): 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 corrected QT (QTc) interval =< 450 ms
• RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): 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 poly(ethylene glycol) (PEG) formulations
• RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): Patients must agree to avoid grapefruit or grapefruit juice and Seville (sour) oranges during the entire study
• RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): Female patients of childbearing potential must have a negative serum or urine pregnancy test
• RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): 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
• RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): 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
• NON-PROGRESSED DIPG OR H3K27M+ THALAMIC DMG (STRATUM 2): Patients with DIPG or H3K27M+thalamic DMG 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 World Health Organization (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 Clinical Laboratory Improvement Act (CLIA) certified laboratory of the investigator’s choice
• NON-PROGRESSED DIPG OR H3K27M+ THALAMIC DMG (STRATUM 2): BSA * Patients must have a BSA >= 0.80 m^2 for dose 5 mg/m^2 * Patients must have a BSA >= 0.65 m^2 for doses of 10mg/m^2 - 22 mg/m^2 * Patients must have a BSA >= 0.50 m^2 for doses of 28 mg/m^2 - 36 mg/m^2
• NON-PROGRESSED DIPG OR H3K27M+ THALAMIC DMG (STRATUM 2): Patient must be able to swallow capsules whole
• NON-PROGRESSED DIPG OR H3K27M+ THALAMIC DMG (STRATUM 2): 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
• NON-PROGRESSED DIPG OR H3K27M+ THALAMIC DMG (STRATUM 2): 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 central nervous system (CNS) malignancy besides standard radiation therapy
• NON-PROGRESSED DIPG OR H3K27M+ THALAMIC DMG (STRATUM 2): Patients must have recovered from the acute treatment-related toxicities (defined as =< grade 1) of radiotherapy prior to entering this study
• NON-PROGRESSED DIPG OR H3K27M+ THALAMIC DMG (STRATUM 2): 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
• NON-PROGRESSED DIPG OR H3K27M+ THALAMIC DMG (STRATUM 2): Absolute neutrophil count >= 1,000/mm^3
• NON-PROGRESSED DIPG OR H3K27M+ THALAMIC DMG (STRATUM 2): Platelets >= 100,000/ mm^3 (unsupported, defined as no platelet transfusion within 7 days, and recovery from post-transfusion nadir)
• NON-PROGRESSED DIPG OR H3K27M+ THALAMIC DMG (STRATUM 2): Hemoglobin >= 8 g/dl (may receive transfusions)
• NON-PROGRESSED DIPG OR H3K27M+ THALAMIC DMG (STRATUM 2): Total bilirubin =< 1.5 times institutional upper limit of normal (ULN)
• NON-PROGRESSED DIPG OR H3K27M+ THALAMIC DMG (STRATUM 2): ALT(SGPT) =< 3 x institutional upper limit of normal
• NON-PROGRESSED DIPG OR H3K27M+ THALAMIC DMG (STRATUM 2): Albumin >= 3 g/dl
• NON-PROGRESSED DIPG OR H3K27M+ THALAMIC DMG (STRATUM 2): Potassium >= LLN
• NON-PROGRESSED DIPG OR H3K27M+ THALAMIC DMG (STRATUM 2): Serum total calcium (correct for serum albumin) or ionized calcium >= LLN
• NON-PROGRESSED DIPG OR H3K27M+ THALAMIC DMG (STRATUM 2): 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 m^2 are eligible * 2 to < 6 years: 0.8 mg/dL * 6 to < 10 years: 1 mg/dL * 10 to < 13 years: 1.2 mg/dL * 13 to < 16 years: 1.5 mg/dL (male), 1.4 mg/dL (female) * >= 16 years: 1.7 mg/dL (male), 1.4 mg/dL (female)
• NON-PROGRESSED DIPG OR H3K27M+ THALAMIC DMG (STRATUM 2): Left ventricular ejection fraction >= 50 by gated radionuclide study OR shortening fraction of >= 27% by echocardiogram
• NON-PROGRESSED DIPG OR H3K27M+ THALAMIC DMG (STRATUM 2): Patient has no ventricular arrhythmias except for benign premature ventricular contractions
• NON-PROGRESSED DIPG OR H3K27M+ THALAMIC DMG (STRATUM 2): Patient has a QTc interval < 450 ms
• NON-PROGRESSED DIPG OR H3K27M+ THALAMIC DMG (STRATUM 2): 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
• NON-PROGRESSED DIPG OR H3K27M+ THALAMIC DMG (STRATUM 2): Patients must agree to avoid grapefruit or grapefruit juice and Seville (sour) oranges during the entire study
• NON-PROGRESSED DIPG OR H3K27M+ THALAMIC DMG (STRATUM 2): Female patients of childbearing potential must have a negative serum or urine pregnancy test
• NON-PROGRESSED DIPG OR H3K27M+ THALAMIC DMG (STRATUM 2): 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
• NON-PROGRESSED DIPG OR H3K27M+ THALAMIC DMG (STRATUM 2): 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

Exclusion Criteria

• RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): Patients who have had > 60 Gy total radiation to the pons (e.g. patients who have received re-irradiation)
• RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): Patients have had prior histone deacetylase (HDAC), deacetylase (DAC), heat shock protein 90 (HSP90) inhibitors for the treatment of their DIPG
• RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): Patients have had valproic acid within 28 days prior to enrollment
• RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): Patients have had prior bone marrow transplant
• RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): Patients have significant acute deterioration in neurologic status in 72 hours prior to enrollment, in the opinion of the treating physician
• RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): Patients have impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of panobinostat; for example severe inflammatory bowel disease
• RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): Patients have diarrhea > Common Terminology Criteria for Adverse Events (CTCAE) grade 2
• RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): 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
• RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): Patients have a history of any other malignancy
• RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): Patients are known to be refractory to red blood cell or platelet transfusions
• RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): Patients who are receiving any other anticancer or investigational drug therapy
• RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): Patients who are required to receive any medication which can prolong the QTc interval
• RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): Female patient is breastfeeding
• RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): 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
• NON-PROGRESSED DIPG OR H3K27M+ THALAMIC DMG (STRATUM 2): Patients who have had > 60 Gy total radiation to the pons (e.g. patients who have received re-irradiation
• NON-PROGRESSED DIPG OR H3K27M+ THALAMIC DMG (STRATUM 2): Patients who have had valproic acid within 28 days prior to enrollment
• NON-PROGRESSED DIPG OR H3K27M+ THALAMIC DMG (STRATUM 2): Patients have significant acute deterioration in neurologic status in 72 hours prior to enrollment, in the opinion of the treating physician
• NON-PROGRESSED DIPG OR H3K27M+ THALAMIC DMG (STRATUM 2): Patients have impairment of GI function or GI disease that may significantly alter the absorption of panobinostat; for example severe inflammatory bowel disease
• NON-PROGRESSED DIPG OR H3K27M+ THALAMIC DMG (STRATUM 2): Patients have diarrhea > CTCAE grade 2
• NON-PROGRESSED DIPG OR H3K27M+ THALAMIC DMG (STRATUM 2): 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
• NON-PROGRESSED DIPG OR H3K27M+ THALAMIC DMG (STRATUM 2): Patients have a history of any other malignancy
• NON-PROGRESSED DIPG OR H3K27M+ THALAMIC DMG (STRATUM 2): Patients are known to be refractory to red blood cell or platelet transfusions
• NON-PROGRESSED DIPG OR H3K27M+ THALAMIC DMG (STRATUM 2): Patients who are receiving any other anticancer or investigational drug therapy
• NON-PROGRESSED DIPG OR H3K27M+ THALAMIC DMG (STRATUM 2): Patients who are required to receive any medication which can prolong the QTc interval
• NON-PROGRESSED DIPG OR H3K27M+ THALAMIC DMG (STRATUM 2): Female patient is breastfeeding
• NON-PROGRESSED DIPG OR H3K27M+ THALAMIC DMG (STRATUM 2): 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