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RTOG 0913   |   02-12-07C
Phase I/II Trial of Concurrent RAD001 (Everolimus) with Temozolomide/Radiation Followed by Adjuvant RAD001/Temozolomide in Newly Diagnosed Glioblastoma

Main Campus
North Coast Cancer
Phase 1
Phase 2
Temozolomide (SCH 52365)

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Phase I
  1. Primary
    • To define the maximum tolerated dose of RAD001 (up to established dose of 10 mg/day) when combined with concurrent radiation and temozolomide in newly diagnosed GBM.
  2. Secondary
    • To characterize the safety profile of RAD001 in combination with radiation and temozolomide.
    Phase II
    1. Primary
      • To determine the efficacy of RAD001 in combination with radiation and temozolomide followed by RAD001 in combination with temozolomide in patients with newly diagnosed GBM as measured by progression-free survival.
    2. Secondary
      • To determine overall survival in newly diagnosed GBM treated with the study regimen.
      • To further evaluate the safety profile of RAD001 in combination with radiation and temozolomide in this patient population.
      • To determine if activation of the Akt/mTOR axis predicts response to RAD001 therapy.
      • To determine if there is an association between tumor MGMT gene methylation status and response to RAD001.

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 and in Section 10).
    • 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 (see Section 10).
    • Diagnosis must be made by surgical excision, either partial or complete. Stereotactic biopsy or CUSA (Cavitron ultrasonic aspirator)-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 MR 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
  • 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.)
  • PT/INR ≤ 1.5.
    • 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 enrollment.
  • Adequate renal function, as defined below:
    • BUN ≤ 30 mg/dl within 14 days prior to step 2 registration
    • Serum creatinine ≤ 1.5 x 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
    • ALT ≤ 2.5 x normal range within 14 days prior to step 2 registration
    • 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. 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 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 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
  • Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the treatment involved in this study may be significantly teratogenic
  • Women who are breast feeding, due to possible adverse effects on the infant
  • Prior allergic reaction to temozolomide
  • Patients who have received prior treatment with an mTOR inhibitor (e.g., sirolimus, temsirolimus, everolimus) or with a known hypersensitivity to these agents or to their excipients
  • Treatment on any other therapeutic clinical protocol
  • 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)
  • Concurrent use of enzyme-inducing anti-epileptic drugs (EIAEDs) (See Appendix V)
    • Patients previously receiving these agents must have discontinued their use at least 14 days prior to step 2 registration
  • History of deep vein thrombosis or pulmonary embolism.

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