RTOG 913 PHASE I/II TRIAL OF CONCURRENT RAD001 (EVEROLIMUS) WITH TEMOZOLOMIDE/RADIATION FOLLOWED BY ADJUVANT RAD001/TEMOZOLOMIDE IN NEWLY DIAGNOSED GLIOBLASTOMA
In summary, overall prognosis of GBM patients remains poor. Although clinical gains have recently been achieved, these have been modest, with a majority of patients succumbing to disease progression within 2 years. New agents need to be identified which can be integrated into and enhance the cytotoxic effects of the current treatment regimen to achieve further clinical gains in this disease. mTOR, which serves as a regulatory hub for both potent pro-survival pathways and tumor angiogenesis, represents a promising target in GBM. Preclinical studies demonstrate ndependent activity of mTOR inhibitors in GBM cell lines, and most importantly, their strong potential to enhance cytotoxic effects of both radiation and chemotherapy. Favorable early clinical experience with RAD001 coupled with preclinical findings provide the rationale for this proposed Phase I/II trial designed to define the toxicity profile and efficacy of adding the mTOR inhibitor RAD001 into the current chemoradiation platform for newly diagnosed GBM patients.
3.1 Conditions for Patient Eligibility (5/1/13, 5/10/13)
3.1.1 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.
3.1.2 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
3.1.3 The tumor must have a supratentorial component
3.1.4 Patients must have recovered from the effects of surgery, postoperative infection, and other
3.1.5 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.
3.1.6 History/physical examination within 14 days prior to step 2 registration
3.1.7 Neurologic examination within 14 days prior to step 2 registration
3.1.8 Documentation of steroid doses within 14 days prior to step 2 registration
3.1.9 Karnofsky performance status >= 70
3.1.10 Age >= 18 years
3.1.11 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.)
3.1.12 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
3.1.13 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
3.1.14 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
3.1.15 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.
3.1.16 For females of child-bearing potential, negative serum pregnancy test within 14 days prior to
step 2 registration
3.1.17 Women of childbearing potential and male participants must practice adequate contraception
3.1.18 Patient must provide study-specific informed consent prior to registration