Everolimus in Treating Children with Recurrent or Refractory Ependymoma or Anaplastic Ependymoma

Inclusion Criteria

• Ependymoma (World Health Organization [WHO] grade II) or anaplastic ependymoma (WHO grade III) that has relapsed or become refractory to standard therapy; patients must have had histologic verification of their malignancy at original diagnosis or time of recurrence
• Lansky >= 50% for patients =< 10 years of age or Karnofsky >= 50% for patients > 10 years of age
• Absolute neutrophil count (ANC) >= 1,500/mm^3
• Platelets >= 100,000/mm^3
• Hemoglobin > 9.0 g/dL
• Total serum bilirubin =< 2.0 mg/dL
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x upper limit of normal (ULN)
• International normalized ratio (INR) =< 2
• Serum creatinine =< 1.5 x ULN
• Fasting serum cholesterol =< 300 mg/dL OR =< 7.75 mmol/L AND fasting triglycerides =< 2.5 x ULN; NOTE: in case one or both of these thresholds are exceeded, the patient can only be included after initiation of appropriate lipid lowering medication
• Signed informed consent obtained prior to any screening procedures
• Patients must have measurable residual disease, defined as tumor that is measurable in two diameters on magnetic resonance imaging (MRI); diffuse leptomeningeal disease is not considered measurable
• Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, and radiotherapy prior to participating in this trial * No prior myelosuppressive chemotherapy for at least 21 days prior to study enrollment * Must not have received craniospinal radiation therapy within 24 weeks prior to study entry and no involved field radiation therapy for 12 weeks prior to study enrollment * If patients received prior monoclonal antibody treatment, at least three half-lives must be elapsed by the time of treatment initiation * No investigational drugs for 4 weeks prior to study enrollment * No prior therapy with mTOR inhibitors (including sirolimus, temsirolimus or everolimus)
• All patients must have had an MRI of the brain and spine that has measurable tumor (not only diffuse leptomeningeal tumor) within two weeks prior to study enrollment; Note: Submission of MRIs for central review is required, but is not required to begin therapy; completion of central review is not required prior to starting treatment
• If available, tumor tissue from either initial diagnosis or subsequent surgery will be submitted on formalin fixed paraffin embedded (FFPE) slides (n = 12) to the Pathology Laboratory at Children’s Medical Center-Dallas for correlative biological studies (including phosphorylated S6235/236, phosphorylated S6240/244, phosphorylated 4EBP1, phosphorylated PRAS40 (pT246), phosphorylated P70S6K, and PTEN expression.); Note: completion of central review is not required prior to starting therapy

Exclusion Criteria

• Known intolerance or hypersensitivity to everolimus or other rapamycin analogs (e.g. sirolimus, temsirolimus)
• Concomitant use of medications known to have strong inhibition or induction of CYP3A enzymes is discouraged and should be discussed with the study principal investigator (PI); note that systemic corticosteroids (e.g., dexamethasone is a CYP3A inducer) are not allowed; inhaled corticosteroids are allowed
• Known impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral everolimus
• Uncontrolled diabetes mellitus as defined by glycosylated hemoglobin (HbA1c) > 8% despite adequate therapy; patients with a known history of impaired fasting glucose or diabetes mellitus (DM) may be included, however blood glucose and antidiabetic treatment must be monitored closely throughout the trial and adjusted as necessary
• Patients who have any severe and/or uncontrolled medical conditions such as: * Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction =< 6 months prior to start of everolimus * Serious uncontrolled cardiac arrhythmia, or any other clinically significant cardiac disease * Symptomatic congestive heart failure of New York Heart Association class III or IV * Active (acute or chronic) or uncontrolled severe infection, * Liver disease such as cirrhosis, decompensated liver disease, and chronic hepatitis (i.e. quantifiable hepatitis B virus [HBV]-deoxyribonucleic acid [DNA] and/or positive hepatitis B surface antigen [HbsAg], quantifiable hepatitis C virus [HCV]-ribonucleic acid [RNA]) * Known severely impaired lung function (spirometry and diffusion capacity of the lung for carbon monoxide [DLCO] 50% or less of normal and oxygen [O2] saturation 88% or less at rest on room air) * Active bleeding diathesis
• Known history of human immunodeficiency virus (HIV) sero-positivity
• Patients who have received live attenuated vaccines within 1 week of start of everolimus and during the study; patient should also avoid close contact with others who have received live attenuated vaccines; examples of live attenuated vaccines include intranasal influenza, measles, mumps, rubella, oral polio, Bacillus Calmette–Guerin (BCG), yellow fever, varicella and TY21a typhoid vaccines
• Patients who have a history of another primary malignancy, with the exceptions of: non-melanoma skin cancer, and carcinoma in situ of the cervix, uteri, or breast from which the patient has been disease free for >= 3 years
• Patients with a history of non-compliance to medical regimens or who are considered potentially unreliable or will not be able to complete the entire study
• Patients who are currently part of or have participated in any clinical investigation with an investigational drug within 1 month prior to dosing
• Pregnant or nursing (lactating) women
• Women of child-bearing potential (WOCBP), defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing of study treatment; women of childbearing potential should be advised to use a highly effective method of contraception while receiving everolimus, and for up to 8 weeks after ending treatment; highly effective contraception is defined as either: * Total abstinence: when this is in line with the preferred and usual lifestyle of the subject; (periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception) * Sterilization: have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment; in case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment * Male partner sterilization (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate); (for female subjects on the study, the vasectomized male partner should be the sole partner for that subject) * Use of a combination of any two of the following: ** Use of oral, injected, implanted or other hormonal methods of contraception ** Placement of an intrauterine device (IUD) or intrauterine system (IUS) ** Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository * In case of use of oral contraception women should have been stable on the oral agent before taking study treatment
• Male Contraception * During the course of the clinical trial, sexually active males must use a condom during intercourse while taking the drug and should not father a child in this period and for up to 8 weeks after stopping treatment * A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid * Female partners of male patients must also be advised to use one of the following contraception methods: use of (1) oral, injected, implanted or other hormonal methods of contraception, or (2) intrauterine device (IUD) or intrauterine system (IUS), or (3) prior male/female sterilization
• Prior to start of everolimus, the following three categories of patients should be tested for hepatitis B viral load and serologic markers, that is, HBV-DNA, HBsAg, hepatitis B surface (HBs) antibody (Ab), and hepatitis B core (HBc) Ab * All patients who currently live in (or have lived in) Asia, Africa, Central and South America, Eastern Europe, Spain, Portugal and Greece * Patients with any of the following risk factors: ** Known or suspected past hepatitis B infection, ** Blood transfusion(s) prior to 1990, ** Current or prior intravenous (IV) drug users, ** Current or prior dialysis, ** Household contact with hepatitis B infected patient(s), ** Current or prior high-risk sexual activity, ** Body piercing or tattoos, ** Mother known to have hepatitis B ** History suggestive of hepatitis B infection, e.g., dark urine, jaundice, right upper quadrant pain ** Additional patients at the discretion of the investigator
• Patients with any of the following risk factors for hepatitis C should be tested using quantitative RNA-polymerase chain reaction (PCR): * Known or suspected past hepatitis C infection (including patients with past interferon ‘curative’ treatment), * Blood transfusions prior to 1990, * Current or prior IV drug users, * Current or prior dialysis, * Household contact of hepatitis C infected patient(s), * Current or prior high-risk sexual activity, * Body piercing or tattoos * At the discretion of the investigator, additional patients may also be tested for hepatitis C