Everolimus (RAD001) for Children With Chemotherapy-Refractory Progressive or Recurrent Low-Grade Gliomas

A Phase II Study of Everolimus (RAD001) for Children With Chemotherapy and/or Radiation-Refractory Progressive or Recurrent Low-Grade Gliomas

The purpose of this research study is to learn if the study drug RAD001 can shrink or slow the growth of low-grade gliomas. Additionally, the safety of RAD001 will be studied. RAD001 is a drug that may act directly on tumor cells by inhibiting tumor cell growth and proliferation.

OBJECTIVES:

Primary

• To determine the response of children with chemotherapy-refractory or progressive low-grade gliomas to everolimus. Secondary
• To evaluate pharmacogenetic polymorphisms of cytochrome P450 3A4 & 3A5 alleles and P-glycoprotein/MDR for their influence on the metabolism of everolimus in this patient population.
• To evaluate the role of Apolipoprotein E genotypes as predictors for development of hyperlipidemia during therapy with everolimus.
• To assess preliminary correlations of response with changes in pharmacodynamic parameters including p70s6 kinase activity in peripheral blood mononuclear cells.
• To describe the toxicity of everolimus when administered to this patient population.
• To characterize the pharmacokinetic profile of everolimus when administered to this patient population.

STATISTICAL DESIGN:

This study used a one-stage design to evaluate response to everolimus. If at least 3 responders are observed in 20 evaluable patients, then everolimus will be considered promising. If the true response rate is 5% (null hypothesis), the chance of concluding the treatment is active is 0.08 (Type I error). If the true response rate is 25% (alternative hypothesis), the chance of concluding the treatment is active is 0.91 (power).

Inclusion Criteria:

• Patients must have histologic verification of one of the eligible diagnoses listed here: Astrocytoma variants; fibrillary, protoplasmic, mixed: Pilocytic astrocytoma; including pilomyxoid variants: Pleomorphic xanthoastrocytoma: infantile desmoplastic astrocytoma: ganglioglioma: oligodendroglial tumors: mixed glioma.
• Patients must have received at least one cancer-directed therapy and patients with allergies to carboplatin must have demonstrated progressive disease after cessation of therapy.
• Must have at least one measurable site of disease that has not been previously irradiated. If the patient has previous irradiation to the marker lesion(s), there must be evidence of progression since radiation treatment.
• Patients must be between 3 years of age and 21 years of age
• Karnofsky Performance Status of 50% or greater for patients less than 10 years of age or Lansky Score of 50% or greater for patients 10 and up.
• Participants must have recovered from the acute toxic effects of all prior chemotherapy or radiotherapy prior to entering the study. Refer to protocol for specific time restrictions with prior therapy completion.
• Adequate bone marrow function as defined in protocol
• Adequate renal function as defined in protocol
• Adequate liver function as defined in protocol
• Patients must have a fasting LDL cholesterol within the normal range per institutional guidelines
• Patients taking cholesterol lowering agent must be on a single medication and on a stable dose for at least 4 weeks
• Fasting serum cholesterol as outlined in protocol
• Patients must not be taking enzyme-inducing anticonvulsants
• Patients may not be currently receiving strong inhibitors of CYP3A4

Exclusion Criteria:

• Presence of NF1 by clinical examination or by genetic testing
• Patients who have had a major surgery or significant traumatic injury within 2 weeks of start of study drug, patients who have not recovered from teh side effects of any major surgery, or patients that may require major surgery during the course of the study
• Patients receiving chronic, systemic treatment with corticosteroids or another immunosuppressive agent. Topical or inhaled are allowed
• Evidence of plexiform neurofibroma, malignant peripheral nerve sheath tumor, or other cancer requiring treatment with chemotherapy or radiation therapy
• Uncontrolled brain or leptomeningeal metastases from plexiform neurofibromas, malignant peripheral nerve sheath tumors, or other cancers (other than astrocytoma variants; fibrillary, protoplasmic, mixed: Pilocytic astrocytoma; including pilomyxoid variants: Pleomorphic xanthoastrocytoma: infantile desmoplastic astrocytoma: ganglioglioma: oligodendroglial tumors: mixed glioma), including patients who continue to require glucocorticoids for control of symptoms related to brain or leptomeningeal metastases.
• Other malignancies within the past three years except for adequately treated carcinoma of the cervix or basal or squamous cell carcinomas of the skin
• Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study (see protocol for examples)
• Known history of HIV seropositivity
• Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of RAD001
• Active, bleeding diathesis or oral anti-vitamin K medication (except low dose coumarin)
• Female patients who are pregnant or breast feeding
• Prior treatment with an mTOR inhibitor
• Known hypersensitivity to RAD001 or other rapamycins or to is excipients
• Dental braces or prosthesis that interferes with tumor imaging
• Patients with a positive history of Hepatitis B or Hepatitis C
• Patients should not receive immunization with attenuated live vaccines within one week of study entry or during study period.