A Study of Panobinostat in Combination With Everolimus for Children and Young Adults With Gliomas

A Phase 2 Study of Panobinostat in Combination With Everolimus for Children and Young Adults With Gliomas Harboring H3.3 or H3.1 K27M Mutation

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).

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.