a study of panobinostat in combination with everolimus for children and young adults with gliomas

Conditions: Glioma; Diffuse Intrinsic Pontine Glioma

Summary: this phase 2 trial will evaluate the activity of panobinostat in combination with everolimus for children with gliomas harboring h3.1 or h3.3k27m mutation, including newly diagnosed high-grade glioma or dipg (diffuse intrinsic pontine glioma) after radiation (stratum a) and recurrent/progressive glioma (grade ii-iv, including dipg) (stratum b).


Eligibility criteria:
inclusion criteria: * all patients and/or a legal guardian must sign institutionally approved written informed consent and assent documents. * patient must be greater than 2 years and less than 30 years * bsa (body surface area) greater than 0.3 m2 * functional status: karnofsky \> 50% for patients \> 16 years of age and lansky \> 50% for patients \< 16 years of age (karnofsky and lansky is a scoring system used to quantify the general well being of cancer patients where 100% represents perfect health and 0% represents death). neurologic deficits in patients with cns tumors must have been relatively stable for a minimum of 7 days. patients who are unable to walk because of paralysis, but who are able to sit in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score. * adequate bone marrow function * adequate liver function * adequate renal and metabolic function * urine protein:creatinine (upc) ratio of \< 1; or a urinalysis that is negative for protein; or 24-hour urine protein level \< 1000 mg/dl * patients must have magnesium \> 1.5 mg/dl and potassium \> 3.5 mmol/l * patients with known seizure disorder must have seizures adequately controlled with non- enzyme inducing antiepileptic medications * no increase in steroid dose within the past 7 days. * stratum a: histological confirmation of a newly diagnosed high-grade glioma or dipg or stratum b: histological confirmation of a recurrent or progressive grade ii-iv glioma (including dipg) \[histology can come from tissue at diagnosis or relapse\] * primary brain or spine tumor are eligible, including tumors with metastases, multiple lesions * patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy. * myelosuppressive chemotherapy: must not have received within 3 weeks (6 weeks if prior nitrosourea). * hematopoietic growth factors: at least 7 days since the completion of therapy with a growth factor, 14 days for long-acting (e.g. peg-filgrastim) * biologic (anti-neoplastic agent): at least 7 days or 3 half-lives (whichever is longer) since the completion of therapy with a biologic agent. * radiation therapy: strata a: ≥ 2 weeks and ≤ to 12 weeks must have elapsed from radiation. strata b: ≥ 2 weeks must have elapsed from focal radiation. * surgery: \> 3 weeks from major surgery. if recent craniotomy, adequate wound healing must be determined by neurosurgical team. * autologous stem cell transplant or rescue: no evidence of active graft vs. host disease and ≥ 4 weeks must have elapsed. * h3k27m mutation: participants must have a mutation in h3.3 k27m or h3.1 k27m as identified by tumor (ffpe or fresh, diagnosis or relapse tissue, but relapse tissue preferred) sequencing, or by clia-certified immunohistochemistry staining positive for h3k27m, as defined by review by u of m neuro-pathology. exclusion criteria: * patients who are breastfeeding, pregnant or refuse to use an effective form of birth control are excluded. abstinence is considered an effective form of birth control. * patients with uncontrolled infection are excluded. * inability to swallow oral pill (panobinostat does not have liquid formulation). * other medications: patients receiving other anti-neoplastic agents are excluded; patients on enzyme-inducing anticonvulsive agents are excluded; patients requiring strong cyp3a4 or pgp inducers or inhibitors are excluded; patients on steroids for symptom management must be on a stable dose for 7 days prior to start of treatment. * allogeneic stem cell transplant: patients within 1 year of allogeneic stem cell transplant, patients with active gvhd or requiring immunosuppression are excluded. * previous hypersensitivity to rapamycin or rapamycin derivatives. * baseline qtc of \>450 msec on ekg or electrolyte imbalance predisposing to qtc prolongation (baseline ≥ grade 1 hypokalemia or hyperkalemia; and baseline ≥ grade 2 ca++, mg++, phosphate abnormalities). repletion/correction is allowed to achieve eligibility. use of qtc prolonging medications will be monitored throughout the trial.

Keywords: h3.1k27m h3.3k27m diffuse intrinsic pontine glioma dipg high-grade glioma pediatric glioma h3k27m panobinostat