Everolimus With and Without Temozolomide in Adult Low Grade Glioma
Condition: Low Grade Glioma; World Health Organization (WHO) Grade II Astrocytomas; Oligodendrogliomas; Mixed Oligoastrocytomas
MeSH terms: Glioma; Astrocytoma; Oligodendroglioma
Intervention: Everolimus; Temozolomide
Intervention description: everolimus at 10 mg daily continuously; Temozolomide will be dosed initially at 150 mg/m2/day for 5 days out of a 28-day cycle. TMZ will be stopped after 12 cycles
Intervention MeSH terms: Everolimus; Temozolomide
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 27.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      The purpose of this study is to find out what effects, good and/or bad, everolimus (RAD001,
      also known as Afinitor®) alone or with temozolomide has on the patient and the patient's
      low-grade glioma. Everolimus is being investigated as an anticancer agent based on its
      potential to prevent tumor cells from growing and multiplying. Specifically, there is a
      protein called mTOR that we think helps many tumors to grow, and everolimus blocks the effect
      of mTOR. Temozolomide is also an anticancer agent that prevents tumor cells from growing and
      multiplying.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Age >= 18 years

          -  Karnofsky performance scale score (KPS) >= 60

          -  Adequate bone marrow function as shown by: Absolute Neutrophil Count (ANC) >= 1.5 x
             10^9/L, Platelets >= 100 x 10^9/L, hemoglobin >= 9.0 g/dL;

          -  Adequate liver function as shown by: Total serum bilirubin ≤ 2.0 mg/dL, alanine
             aminotransferase (ALT) and aspartate aminotransferase (AST) <=2.5x upper limit of
             normal (ULN), International Normalized Ratio (INR) <= 2;

          -  Adequate renal function: serum creatinine <=1.5 x ULN;

          -  Fasting serum cholesterol <= 300 mg/dL OR <= 7.75 mmol/L AND fasting triglycerides <=
             2.5x 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 prior to any screening procedures

          -  Histologically proven supratentorial low-grade glioma at initial diagnosis; pathology
             must have been reviewed by University of California, 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 Isocitrate dehydrogenase
             1 (IDH1) and/or Isocitrate dehydrogenase 2 (IDH2) mutation of any type.

          -  Results of 1p/19q chromosomal status and p-PRAS40 testing must be available to permit
             treatment selection.

          -  Evaluable disease

          -  Must begin treatment within 120 days of surgical procedure

        Exclusion Criteria:

          -  No prior tumor treatment except for surgery at diagnosis, and must have adequately
             recovered from surgery

          -  Known intolerance or hypersensitivity to everolimus or other rapamycin analogs (e.g.
             sirolimus, temsirolimus) or to temozolomide

          -  Known impairment of gastrointestinal (GI) function or GI disease that may
             significantly alter the absorption of oral everolimus or temozolomide

          -  Uncontrolled diabetes mellitus as defined by 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;

          -  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-DNA and/or positive Hepatitis B
             Surface Antigen (HbsAg), quantifiable hepatitis C virus (HCV-RNA); known severely
             impaired lung function (spirometry and Diffusing capacity of the lungs for carbon
             monoxide (DLCO) 50% or less of normal and 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 HIV seropositivity;

          -  Positive serological test results for hepatitis B

          -  Positive serological test result for hepatitis C

          -  Recipients of live attenuated vaccines within 1 week of start of treatment and during
             the study. 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;

          -  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;

          -  History of non-compliance to medical regimens or who are considered potentially
             unreliable or will not be able to complete the entire study;

          -  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