Everolimus with or without Temozolomide in Treating Patients with Newly-Diagnosed Low-Grade Gliomas

Inclusion Criteria

• Karnofsky performance status (KPS) >= 60
• Absolute neutrophil count (ANC) >= 1.5 x 10^9/L
• Platelets >= 100 x 10^9/L
• Hemoglobin (Hb) >= 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 with confirmed reduction of lab values to within eligibility parameters
• Signed informed consent obtained prior to any screening procedures
• Patients must have histologically proven supratentorial low-grade glioma at initial diagnosis; pathology must have been reviewed by University of California at San Francisco (UCSF) neuropathology; eligible low-grade gliomas include: astrocytoma, oligodendroglioma and mixed oligoastrocytoma; pilocytic astrocytomas are excluded
• Patient’s tumor must have documentation of the presence of an IDH-1 and/or IDH-2 mutation of any type
• Results of ATRX and/or 1p/19q chromosomal status: if ATRX is lost, 1p/19q status is not required; if ATRX is intact, 1p/19q chromosomal status must be available to permit treatment selection
• Results of pRAS40 testing
• Patients must have evaluable disease; patients must begin treatment within 120 days of their surgical procedure

Exclusion Criteria

• Patients may not have had any prior tumor treatment except for surgery, and must have adequately recovered from surgery
• Known intolerance or hypersensitivity to everolimus or other rapamycin analogs (e.g. sirolimus, temsirolimus)
• Known impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral everolimus
• Uncontrolled diabetes mellitus as defined by hemoglobin A1c (HbA1c) > 8.0% 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 virus surface antigen [HbsAg], quantifiable hepatitis C virus [HCV]-ribonucleic acid [RNA]) * Known severely impaired lung function (spirometry and diffusing 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
• Chronic treatment with corticosteroids or other immunosuppressive agents; topical or inhaled corticosteroids are allowed, and treatment with low dose Decadron (=< 3mg daily) is allowed
• Known history of human immunodeficiency virus (HIV) seropositivity
• Positive serological test results for hepatitis B
• Positive serological test result for hepatitis C
• 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, uterus, or breast, unless 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 therapeutic 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, who are not willing to use adequate methods of contraception during the study and for 8 weeks after the end of treatment; Women are considered post-menopausal and not of child-bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks prior to randomization; in the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child-bearing potential
• Male patients whose sexual partner(s) are WOCBP who are not willing to use adequate contraception, during the study and for 8 weeks after the end of treatment