Phase II Trial of RAD001 in Patients With Recurrent Low Grade Glioma

Inclusion Criteria:

• Patients must have a Karnofsky performance status of > 60
• Patients must have a life expectancy > 8 weeks
• Adequate bone marrow function as shown by: ANC ≥ 1.5 x 109/L, Platelets ≥ 100 x 109/L, Hb >9 g/dL
• Adequate liver function as shown by:
• serum bilirubin ≤ 1.5 x ULN
• INR < 1.3 (Anticoagulation is allowed if target INR ≤ 1.5 on a stable dose of warfarin or on a stable dose of LMW heparin for > 2 weeks at the time of registration)
• ALT and AST ≤ 2.5x ULN
• Adequate renal function: 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.
• Patients must have histologically proven intracranial low-grade glioma at initial diagnosis.
• Patients must have unequivocal evidence for tumor recurrence or progression by histology as determined by review of pathology by an attending neuro-pathologist at UCSF
• If most recent histology shows progression to high grade glioma, patients must have had prior radiotherapy in order to be eligible
• Paraffin-embedded sections of tissue acquired from surgery at the time of suspected recurrence must be available for analysis
• Patients must have evidence for tumor recurrence or progression by MRI as determined by radiographic review of images by an attending neuro-oncologist or neuro-radiologist at UCSF
• An MRI must be used throughout the period of protocol treatment for tumor measurement
• Patients may have had treatment (including radiotherapy) for any number of relapses prior to this recurrence
• Patients must be at least 4 weeks from the completion of any radiation therapy
• Patients must be less than 4 months from the surgical procedure for this recurrence

• Patients must have recovered from the toxic effects of prior therapy:

  • 4 weeks from any investigational agent.
  • 4 weeks from prior cytotoxic therapy (except 6 weeks from nitrosoureas, 3 weeks from procarbazine, 3 weeks from vincristine)
  • 3 weeks for non-cytotoxic or biologic agents e.g., interferon, tamoxifen, thalidomide, cis-retinoic acid, etc

Exclusion Criteria:

• Patients, who have not recovered from the side effects of a major surgery or significant traumatic injury 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 corticosteroids, and treatment with low dose Decadron (£ 6mg daily) are allowed.
• Other malignancies within the past 3 years except for adequately treated carcinoma of the cervix or basal or squamous cell carcinomas of the skin.
• Other than surgery, patients may not have therapy for this recurrence (including radiation). Supportive care such as steroids or anti-epileptics does not constitute treatment of recurrence
• Patients must not be on an enzyme inducing antiepileptic agent within 5 days of starting protocol therapy
• Patients must not have any significant medical illnesses that in the investigator's opinion cannot be adequately controlled with appropriate therapy or would compromise the patient's ability to tolerate this therapy.
• Patients with a history of any other cancer (except non-melanoma skin cancer or carcinoma in-situ of the cervix), unless in complete remission and off of all therapy for that disease for a minimum of 3 years are ineligible.
• Patients should not receive immunization with attenuated live vaccines within one week of study entry or during study period
• Uncontrolled brain or all leptomeningeal metastases, including patients who continue to require glucocorticoids for brain or leptomeningeal metastases
• Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as:
• Symptomatic congestive heart failure of New York heart Association Class III or IV
• unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction within 6 months of start of study drug, serious uncontrolled cardiac arrhythmia or any other clinically significant cardiac disease
• Impaired lung function: Oxygen saturation 88% or less at rest on room air by Pulse Oximetry. If O2 saturation is ≤ 88% at rest, further pulmonary function tests (PFTs) should be ordered to confirm normal pulmonary function and eligibility.
• uncontrolled diabetes as defined by fasting serum glucose >1.5 x ULN
• active (acute or chronic) or uncontrolled severe infections
• liver disease such as cirrhosis, chronic active hepatitis or chronic persistent hepatitis
• A known history of HIV seropositivity
• Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of RAD001 (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection)
• Patients with an active, bleeding diathesis
• Female patients who are pregnant or breast feeding, or adults of reproductive potential who are not using effective birth control methods.
• Patients who have received prior treatment with an mTOR inhibitor (sirolimus, temsirolimus, everolimus).
• Patients with a known hypersensitivity to RAD001 (everolimus) or other rapamycins (sirolimus, temsirolimus) or to its excipients