PNOC 001: Phase II Study of Everolimus for Recurrent or Progressive Low-grade Gliomas in Children

• -Patients must have radiographic progressive or recurrent confirmed world health organization (WHO) grade I or II astrocytomas, that was confirmed histologically. Progressive or recurrent disease should be based on MRI according to the definition below.

• Eligible histologies:

⁃ Pilocytic Astrocytoma - 90600112

⁃ Astrocytoma, Low Grade (Fibrillary astrocytoma, WHO Grade 2) - 10065886

⁃ Astrocytoma, Low Grade (Low-grade Astrocytoma, not otherwise specified (NOS), WHO Grade 2) - 10003571

∙ Tissue from the initial diagnosis or recurrence must be made available for correlative testing.

‣ Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least two dimensions on MRI.

‣ Patients may have had treatment (chemotherapy and/or radiotherapy) for any number of relapses prior to this recurrence.

‣ Patients must have received their last dose of myelosuppressive anticancer chemotherapy at least three (3) weeks prior to study registration or at least six (6)weeks of nitrosourea.

‣ Patients must have received their last dose of other investigational or biological agent \> 7 days prior to study entry.

• For agents that have known adverse events occurring beyond 7 days after administration, this period should be extended beyond the time during which adverse events are known to occur. This should be discussed with the study chair.

⁃ If patients received prior monoclonal antibody treatment, at least three half-lives must be elapsed by the time of treatment initiation. These patients should also be discussed with the study chair.

⁃ Patients must have received their last fraction of craniospinal or focal radiation to primary tumor or other sites \>12 weeks (3 months) prior to registration.

‣ -Age ≥3 and ≤21 years.

⁃ Because no dosing or adverse event data are currently available on the use of everolimus in patients \<3 years of age, these young children are excluded from this study.

∙ Life expectancy of greater than 8 weeks.

‣ Patients must be able to swallow pills.

‣ Patient must have a Karnofsky (if ≥ 16 years of age) or Lansky Performance score (if ≤ 16 years of age) of ≥50 by the time of registration.

‣ Patients must have adequate bone marrow function (ANC ≥ 1,000/mm3, platelet count of ≥ 100,000/mm3, and hemoglobin ≥ 9 gm/dL) before starting therapy. Eligibility level for hemoglobin may be reached by transfusion.

‣ International Normalized Ratio (INR) ≤1.5. (Anticoagulation is allowed if target INR ≤ 1.5 on a stable dose of warfarin or on a stable dose of low molecular weight (LMW) heparin for \>2 weeks at time of randomization).

‣ Patients must have adequate liver function (SGPT/alanine aminotransferase (ALT) ≤ 2.5 times ULN and bilirubin ≤ 1.5 times ULN) before starting therapy.

‣ Patients must have adequate renal function (serum creatinine ≤ 1.5 times institutional ULN for age or Glomerular filtration rate (GFR) ≥ 70 ml/min/1.73 m2) before starting therapy.

‣ Patients must have cholesterol level \<350 mg/dL and triglycerides \< 400 mg/dL before starting therapy. In case one or both of these are exceeded, the patient can only be included after initiation of appropriate lipid lowering medication and documentation of cholesterol \< 350mg/dL and triglycerides \< 400mg/dl before start of therapy.

‣ Patients must have normal pulmonary function testing for age based on pulse oximetry.

‣ The effects of everolimus on the developing human fetus at the recommended therapeutic dose are unknown. For this reason and because everolimus are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.

‣ Female patients of child bearing potential must not be breastfeeding or pregnant as evidenced by a negative pregnancy test.