Everolimus, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma
RATIONALE: Everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking some of the blood flow to the tumor. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving everolimus together with temozolomide and radiation therapy may kill more tumor cells.
PURPOSE: This phase I/II trial is studying the side effects and best dose of everolimus when given together with temozolomide and radiation therapy in treating patients with newly diagnosed glioblastoma.
|Brain and Central Nervous System Tumors||Drug: everolimus Drug: temozolomide Radiation: radiation||Phase 1 Phase 2|
|Study Design:||Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
|Official Title:||Phase I/II Evaluation of Everolimus (RAD001), Radiation and Temozolomide (TMZ) Followed by Adjuvant Temozolomide and Everolimus in Newly Diagnosed Glioblastoma|
- Maximum Tolerated Dose (MTD) of Everolimus (RAD001) in Combination With Temozolomide (TMZ) and 3D-conformal Radiotherapy (RT) or Intensity-modulated Radiotherapy (IMRT) Followed by Adjuvant TMZ With or Without RAD001 (Phase I) [ Time Frame: Up to 49 days ]Patients were assessed during RT for dose-limiting toxicities (DLT), which were defined as failure to deliver greater than 75% of the planned doses of TMZ or RAD001 during RT, interruption of RT for more than 5 days because of toxicity, or the following: >= Grade 3 diarrhea or skin rash; >= Grade 4 neutropenia, leukopenia, or thrombocytopenia; >= Grade 4 hypertriglyceridemia, hypercholesterolemia, or hyperglycemia despite optimal medial management, other >= 3 non-hematologic events; or >= Grade 4 radiation dermatitis. Maximum tolerated dose (MTD) was defined a priori as the highest dose level at which 0 or 1 of 6 patients developed DLTs. The number of patients who developed DLTs are reported here by dose level, with the MTD reported in the statistical analysis section.
- Overall Survival at 12 Months (Phase II) [ Time Frame: at 12 months ]The primary endpoint is overall survival at 12 months (OS12) after entry into this study. The proportion of successes will be estimated using the binomial point estimator (number of successes divided by the total number of evaluable patients) and the binomial 95% confidence interval estimated. A patient who is evaluable and survive more than 12 months (i.e. 365 days or more) after start of therapy will be classified as a "success". Patients who die within 12 months after start of therapy will be considered to have "failed".
- Response Rate, as Measured in Patients Receiving FLT-PET Imaging (Phase II) [ Time Frame: Up to 5 years ]The response rate is defined as the percentage of patients receiving F-fluorothymidine positron emission tomography (FLT-PET) imaging whose cancer shrinks or disappears after treatment. A reduction in standardized uptake value (SUV) of 30% or greater in the T1-post-gadolinium scan volume of interest (T1-gad VOI) or the total tumor VOI will be considered a responsive tumor.
- Time to Progression (Phase II) [ Time Frame: Up to 5 years ]Time-to-disease progression is defined as the time from start of study therapy to documentation of disease progression. Patients who die without documentation of progression will be considered to have had tumor progression at the time of death unless there is documented evidence that no progression occurred before death. Patients who fail to return for evaluation after beginning therapy will be censored for progression on the last day of therapy. Patients who experience major treatment violations will be censored for progression on the date of treatment violation occurred. The time-to-progression distribution will be estimated using the Kaplan-Meier method. Progression is defined as at least a 25% increase in product of perpendicular diameters of contrast enhancement or mass or unequivocal increase in size of contrast enhancement or increase in mass effect as agreed upon independently by primary physician and quality control physicians or appearance of new lesions.
- Progression-free-survival at 6 Months (Phase II) [ Time Frame: at 6 months ]Progression-free-survival at 6 months: is the proportion of patients alive and progression-free at 6 months after start of regimen. This proportion will be estimated using the binomial point estimator and the binomial 95% confidence interval estimated. Progression is defined as at least a 25% increase in product of perpendicular diameters of contrast enhancement or mass or unequivocal increase in size of contrast enhancement or increase in mass effect as agreed upon independently by primary physician and quality control physicians or appearance of new lesions.
- Overall Survival Time [ Time Frame: Up to 15 years ]Overall survival: The overall survival or survival time is defined as the time from registration to death due to any cause. The distribution of overall survival will be estimated using the method of Kaplan-Meier method.
|Study Start Date:||March 2009|
|Primary Completion Date:||January 2012 (Final data collection date for primary outcome measure)|
Experimental: Everolimus (RAD001), Radiation (RT), Temozolomide (TMZ)
Patients receive oral everolimus and oral temozolomide and 3D-conformal radiotherapy or IMRT as in phase I. Patients will undergo a 4-6 week rest period in course 2 and then proceed to adjuvant therapy.
Adjuvant therapy with everolimus and temozolomide (courses 3-8): Patients receive oral everolimus and oral temozolomide as in phase I.
Adjuvant therapy with everolimus alone (courses 9 and all subsequent courses): Patients receive oral everolimus as in phase I.
All patients undergo fludeoxyglucose (FDG)- or fluorothymidine-labeled PET/CT scans at baseline and periodically during treatment.
|Drug: everolimus Drug: temozolomide Radiation: radiation|
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Please refer to this study by its ClinicalTrials.gov identifier: NCT00553150
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|Study Chair:||Jann N. Sarkaria, MD||Mayo Clinic|