Ignite Creation Date:
2025-12-24 @ 5:09 PM
Ignite Modification Date:
2026-01-31 @ 11:35 AM
Study NCT ID:
NCT00553150
Status:
COMPLETED
Last Update Posted:
2020-02-13
First Post:
2007-11-02
Is Gene Therapy:
True
Has Adverse Events:
True
Brief Title:
Everolimus, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma
Sponsor:
Alliance for Clinical Trials in Oncology
Organization:
Study Overview
Official Title:
Phase I/II Evaluation of Everolimus (RAD001), Radiation and Temozolomide (TMZ) Followed by Adjuvant Temozolomide and Everolimus in Newly Diagnosed Glioblastoma
Status:
COMPLETED
Status Verified Date:
2020-02
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
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.
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.
* 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.
Study Oversight
Has Oversight DMC:
False
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?: