Everolimus, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma Multiforme

OBJECTIVES:

Primary

• To define the maximum tolerated dose of everolimus (up to an established dose of 10 mg/day) when combined with concurrent radiotherapy and temozolomide in patients with newly diagnosed glioblastoma multiforme. (Phase I)
• To determine the efficacy of everolimus in combination with radiotherapy and temozolomide followed by adjuvant everolimus in combination with temozolomide, as measured by progression-free survival, in these patients. (Phase II)

Secondary

• To characterize the safety profile of everolimus in combination with radiotherapy and temozolomide in these patients. (Phase I)
• To determine the overall survival of these patients. (Phase II)
• To further evaluate the safety profile of everolimus in combination with radiotherapy and temozolomide in these patients. (Phase II)
• To determine if activation of the Akt/mTOR axis predicts response to everolimus. (Phase II)
• To determine if there is an association between tumor MGMT gene methylation status and response to everolimus. (Phase II)

OUTLINE: This is a multicenter, phase I, dose-escalation study of everolimus followed by a phase II, randomized study.

After completion of study treatment, patients are followed up every 3 months for 1 year, every 4 months for 1 year, and then every 6 months thereafter.

Inclusion criteria

• Histologically proven diagnosis of glioblastoma (WHO grade IV) confirmed by central pathology review prior to Step 2 registration. Since gliosarcoma is a variant of glioblastoma, gliosarcoma is also an eligible diagnosis.
• Tumor tissue available for correlative studies (Required only in phase II portion, as described below).

• Patients must have at least 1 block of tissue; if a block cannot be submitted, two tissue specimens punched with a skin punch (2 mm diameter) from the tissue block containing the tumor may be submitted.
• Diagnosis must be made by surgical excision, either partial or complete. Stereotactic biopsy or Cavitron ultrasonic aspirator (CUSA)-derived tissue is not allowed for patients on Phase II, as it will not provide sufficient tissue for the required MGMT and pAKT/pMTOR analyses.
• The tumor must have a supratentorial component
• Patients must have recovered from the effects of surgery, postoperative infection, and other complications.
• A diagnostic contrast-enhanced MRI or CT scan (if MRI is not available due to non-compatible devices) of the brain must be performed preoperatively and postoperatively. The postoperative scan must be done within 28 days prior to step 2 registration, ,preferably within 96 hours of surgery. Preoperative and postoperative scans must be the same type.

• Patients unable to undergo MRI imaging because of non-compatible devices can be enrolled, provided pre- and post-operative contrast enhanced CT scans are obtained and are of sufficient quality.
• History/physical examination within 14 days prior to step 2 registration
• Neurologic examination within 14 days prior to step 2 registration
• Documentation of steroid doses within 14 days prior to step 2 registration
• Karnofsky performance status ≥ 70
• Age ≥ 18 years
• Complete blood count (CBC)/differential obtained within 14 days prior to step 2 registration, with adequate bone marrow function defined as follows:

• Absolute neutrophil count (ANC) ≥ 1,800 cells/mm3;
• Platelets ≥ 100,000 cells/mm3;
• Hemoglobin ≥ 10.0 g/dl (Note: The use of transfusion or other intervention to achieve Hgb ≥ 10.0 g/dl is acceptable.)
• Prothrombin time/international normalized ratio (PT INR) ≤ 1.5 for patients not on warfarin confirmed by testing within 14 days prior to step 2 registration.

Patients on full-dose anticoagulants (eg, warfarin or low molecular weight heparin) must meet both of the following criteria:

• No active bleeding or pathological condition that carries a high risk of bleeding (eg, tumor involving major vessels or known varices)
• In-range INR (between 2 and 3) on a stable dose of oral anticoagulant or on a stable dose of low molecular weight heparin
• Adequate renal function, as defined below:

• Blood urea nitrogen (BUN) ≤ 30 mg/dl within 14 days prior to step 2 registration
• Serum creatinine ≤ 1.5 x upper limit of normal (ULN) within 14 days prior to step 2 registration
• Adequate hepatic function, as defined below:

• Bilirubin ≤ 1.5 x normal range within 14 days prior to step 2 registration
• Alanine aminotransferase (ALT) ≤ 2.5 x normal range within 14 days prior to step 2 registration
• Aspartate aminotransferase (AST) ≤ 2.5 x normal range within 14 days prior to step 2 registration
• Fasting serum cholesterol ≤300 mg/dL OR ≤7.75 mmol/L AND fasting triglycerides ≤ 2.5 x ULN (upper limit of normal). Note: If one or both of these thresholds are exceeded, the patient can only be included after initiation of appropriate lipid lowering medication.
• For females of child-bearing potential, negative serum pregnancy test within 14 days prior to step 2 registration
• Women of childbearing potential and male participants must practice adequate contraception
• Patient must provide study-specific informed consent prior to registration

Exclusion criteria

• Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 3 years (For example, carcinoma in situ of the breast, oral cavity, or cervix are all permissible)
• Recurrent or multifocal malignant glioma
• Metastases detected below the tentorium or beyond the cranial vault
• Prior use of Gliadel wafers or any other intratumoral or intracavitary treatment
• Prior radiotherapy to the head or neck (except for T1 glottic cancer), resulting in overlap of radiation therapy fields
• Prior chemotherapy or radiosensitizers for cancer of the head and neck region; note that prior chemotherapy for a different cancer is allowable, except prior temozolomide or RAD001.
• Prior radiation therapy or chemotherapy for glioblastoma
• Severe, active co-morbidity, defined as follows:

• Symptomatic congestive heart failure of New York heart Association Class III or IV
• Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction within the last 6 months, serious uncontrolled cardiac arrhythmia or any other clinically significant cardiac disease
• Severely impaired lung function as defined as spirometry and diffusing capacity of the lungs for carbon monoxide (DLCO) that is 50% of the normal predicted value and/or 02 saturation that is 88% or less at rest on room air
• Uncontrolled diabetes as defined by fasting serum glucose >1.5 x ULN
• Active (acute or chronic) or uncontrolled severe infections requiring intravenous antibiotics
• Liver disease such as cirrhosis, chronic active hepatitis or chronic persistent hepatitis
• Acquired immune deficiency syndrome (AIDS) based upon current Centers for Disease Control and Prevention (CDC) definition or known HIV seropositivity; note, however, that HIV testing is not required for entry into this protocol. The need to exclude patients with HIV/AIDS from this protocol is necessary because the treatments involved in this protocol may be significantly immunosuppressive.
• Active connective tissue disorders, such as lupus or scleroderma, that in the opinion of the treating physician may put the patient at high risk for radiation toxicity
• Other major medical illnesses or psychiatric impairments that in the investigator's opinion will prevent administration or completion of protocol therapy