Everolimus, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma
- Conditions
- Brain and Central Nervous System Tumors
- Interventions
- Registration Number
- NCT00553150
- Lead Sponsor
- Alliance for Clinical Trials in Oncology
- Brief Summary
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.
- Detailed Description
OBJECTIVES:
* To determine the maximum tolerated dose (MTD) of everolimus in combination with temozolomide and 3D-conformal radiotherapy or intensity-modulated radiotherapy (IMRT) followed by adjuvant temozolomide with or without everolimus in patients with newly diagnosed glioblastoma. (Mayo Clinic Rochester \[MCR\] AND Mayo Clinic Jacksonville \[MCJ\] patients only) (Phase I)
* To assess and describe the adverse events of everolimus in combination with temozolomide and 3D-conformal radiotherapy or IMRT followed by adjuvant temozolomide with or without everolimus in patients with newly diagnosed glioblastoma. (MCR and MCJ patients only) (Phase I)
* To assess treatment effectiveness of everolimus in combination with temozolomide and 3D-conformal radiotherapy or IMRT followed by adjuvant temozolomide with or without everolimus, until progression, in patients with newly diagnosed glioblastoma. (all North Central Cancer Treatment Group \[NCCTG\] patients) (Phase II)
* To characterize the toxicities of everolimus in combination with temozolomide and 3D-conformal radiotherapy or IMRT followed by adjuvant temozolomide with or without everolimus in patients with newly diagnosed glioblastoma. (all NCCTG patients) (Phase II)
* Evaluate whether suppression of fludeoxyglucose F18 (18FDG) uptake in tumor and normal brain can be used to determine a biologically effective dose for efficient penetration of everolimus through the blood-brain barrier. (MCR and MCJ patients only) (Phase I)
* Correlate everolimus levels with 18FDG uptake suppression in tumor and normal brain. (MCR and MCJ patients only) (Phase I)
* Assess the relationship between efficacy endpoints (i.e., survival, progression-free survival, and response) and changes in 3'-deoxy-3'-\[18F\]fluorothymidine (18F-FLT) uptake for patients treated at MCR. (all NCCTG patients) (Phase II)
* Assess the relationship between efficacy endpoints (i.e., survival, progression-free survival, and response), and phospho-Akt, PTEN status, and MGMT expression and promoter methylation status. (all NCCTG patients) (Phase II)
* Assess the relationship between efficacy endpoints (i.e., survival, progression-free survival, and response) and baseline gene expression signatures from paraffin embedded pre-treatment tumor samples. (all NCCTG patients) (Phase II)
* Correlate gene expression between paraffin and frozen samples. (all NCCTG patients) (Phase II)
* Evaluate potential mechanisms of therapy resistance in recurrent tumor samples obtained at the time of surgery for recurrent disease. (Phase I and II)
OUTLINE: This is a multicenter, phase I dose-escalation study of everolimus followed by a phase II study.
* Phase I (Mayo Clinic Rochester \[MCR\] AND Mayo Clinic Jacksonville \[MCJ\] ONLY):
* Concurrent therapy (courses 1 and 2): Patients receive oral everolimus once weekly in weeks 1-7 or 1-8 and oral temozolomide once daily in weeks 2-7 or 3-8. Patients also undergo radiotherapy 5 days a week in either weeks 2-7 or 3-8. Four to six weeks later, patients proceed to adjuvant therapy. This rest period is defined as course 2.
* Adjuvant therapy with everolimus and temozolomide (courses 3-8): Patients receive oral everolimus on days 1, 8, 15, and 22 and oral temozolomide on days 1-5. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.
* Adjuvant therapy with everolimus alone (courses 9 and all subsequent courses): Patients receive oral everolimus on days 1, 8, 15, and 22. Treatment repeats every 28 days in the absence of disease progression our unacceptable toxicity.
* Phase II (Open to MCR center ONLY) (All North Central Cancer Treatment Group \[NCCTG\] centers closed to accrual as of 02/17/11):
* Concurrent therapy (courses 1 and 2): 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.
Patients undergo blood sample collection periodically for pharmacological studies. Samples are analyzed for everolimus blood levels and correlated with 18FDG uptake suppression in tumor and normal brain via LC-MSMS. Previously collected tumor tissue are analyzed for protein biomarkers including PTEN gene expression levels via fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) and phosphorylation on Ser473 and Ser308 of Akt and MGMT expression and promoter methylation via IHC. Samples are also analyzed for DNA sequencing. Some samples are banked for future studies.
After completion of study treatment, patients are followed every 2 months for 1 year, every 3 months for 1 year, and then every 6 months for 3 years.
PROJECTED ACCRUAL: A total of 138 patients (24 patients in phase I and 114 patients in phase II) will be accrued for this study.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 122
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Everolimus (RAD001), Radiation (RT), Temozolomide (TMZ) temozolomide 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. Everolimus (RAD001), Radiation (RT), Temozolomide (TMZ) radiation 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. Everolimus (RAD001), Radiation (RT), Temozolomide (TMZ) everolimus 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.
- Primary Outcome Measures
Name Time Method Overall Survival at 12 Months (Phase II) 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".
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) 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.
- Secondary Outcome Measures
Name Time Method Time to Progression (Phase II) 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.
Response Rate, as Measured in Patients Receiving FLT-PET Imaging (Phase II) 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.
Progression-free-survival at 6 Months (Phase II) 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 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.
Trial Locations
- Locations (176)
Mayo Clinic Scottsdale
🇺🇸Scottsdale, Arizona, United States
Saint Francis/Mount Sinai Regional Cancer Center at Saint Francis Hospital and Medical Center
🇺🇸Hartford, Connecticut, United States
Mayo Clinic - Jacksonville
🇺🇸Jacksonville, Florida, United States
Saint Alphonsus Cancer Care Center at Saint Alphonsus Regional Medical Center
🇺🇸Boise, Idaho, United States
Illinois CancerCare - Bloomington
🇺🇸Bloomington, Illinois, United States
St. Joseph Medical Center
🇺🇸Bloomington, Illinois, United States
Graham Hospital
🇺🇸Canton, Illinois, United States
Illinois CancerCare - Canton
🇺🇸Canton, Illinois, United States
Illinois CancerCare - Carthage
🇺🇸Carthage, Illinois, United States
Memorial Hospital
🇺🇸Carthage, Illinois, United States
Scroll for more (166 remaining)Mayo Clinic Scottsdale🇺🇸Scottsdale, Arizona, United States