Everolimus, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma Multiforme

Phase 1

Completed

Conditions: Brain and Central Nervous System Tumors

Interventions: Drug: concurrent RAD001 10 mg/day
Drug: concurrent temozolomide
Radiation: Radiation therapy
Drug: concurrent RAD001 2.5 mg/day
Drug: concurrent RAD001 5 mg/day
Drug: post-radiation RAD001 10 mg/day
Drug: post-radiation temozolomide

Registration Number: NCT01062399

Lead Sponsor: Radiation Therapy Oncology Group

Brief Summary: RATIONALE: Everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor 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 and to see how well it works in treating patients with newly diagnosed glioblastoma multiforme.

Detailed Description: OBJECTIVES:

Primary

* To define the maximum tolerated dose of everolimus (up to an established dose of 10 mg/day) when combined with concurrent radiotherapy and temozolomide in patients with newly diagnosed glioblastoma multiforme. (Phase I)

* To determine the efficacy of everolimus in combination with radiotherapy and temozolomide followed by adjuvant everolimus in combination with temozolomide, as measured by progression-free survival, in these patients. (Phase II)

Secondary

* To characterize the safety profile of everolimus in combination with radiotherapy and temozolomide in these patients. (Phase I)

* To determine the overall survival of these patients. (Phase II)

* To further evaluate the safety profile of everolimus in combination with radiotherapy and temozolomide in these patients. (Phase II)

* To determine if activation of the Akt/mTOR axis predicts response to everolimus. (Phase II)

* To determine if there is an association between tumor MGMT gene methylation status and response to everolimus. (Phase II)

OUTLINE: This is a multicenter, phase I, dose-escalation study of everolimus followed by a phase II, randomized study.

After completion of study treatment, patients are followed up every 3 months for 1 year, every 4 months for 1 year, and then every 6 months thereafter.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 279

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Ph I: RT + TMZ + RAD001 2.5 mg/day	Radiation therapy	Radiation therapy (RT), concurrent temozolomide (TMZ), and concurrent RAD001 2.5 mg/day followed by post-radiation temozolomide and post-radiation RAD001 10 mg/day.
Ph I: RT + TMZ + RAD001 2.5 mg/day	concurrent RAD001 2.5 mg/day	Radiation therapy (RT), concurrent temozolomide (TMZ), and concurrent RAD001 2.5 mg/day followed by post-radiation temozolomide and post-radiation RAD001 10 mg/day.
Ph I: RT + TMZ + RAD001 2.5 mg/day	post-radiation RAD001 10 mg/day	Radiation therapy (RT), concurrent temozolomide (TMZ), and concurrent RAD001 2.5 mg/day followed by post-radiation temozolomide and post-radiation RAD001 10 mg/day.
Ph I: RT + TMZ + RAD001 5 mg/day	Radiation therapy	Radiation therapy, concurrent temozolomide, and concurrent RAD001 5 mg/day followed by post-radiation temozolomide and post-radiation RAD001 10 mg/day.
Ph I: RT + TMZ + RAD001 5 mg/day	concurrent RAD001 5 mg/day	Radiation therapy, concurrent temozolomide, and concurrent RAD001 5 mg/day followed by post-radiation temozolomide and post-radiation RAD001 10 mg/day.
Ph I: RT + TMZ + RAD001 5 mg/day	post-radiation RAD001 10 mg/day	Radiation therapy, concurrent temozolomide, and concurrent RAD001 5 mg/day followed by post-radiation temozolomide and post-radiation RAD001 10 mg/day.
Ph I: RT + TMZ + RAD001 10 mg/day	concurrent RAD001 10 mg/day	Radiation therapy, concurrent temozolomide, and concurrent RAD001 10 mg/day followed by post-radiation temozolomide and post-radiation RAD001 10 mg/day.
Ph I: RT + TMZ + RAD001 10 mg/day	Radiation therapy	Radiation therapy, concurrent temozolomide, and concurrent RAD001 10 mg/day followed by post-radiation temozolomide and post-radiation RAD001 10 mg/day.
Ph I: RT + TMZ + RAD001 10 mg/day	post-radiation RAD001 10 mg/day	Radiation therapy, concurrent temozolomide, and concurrent RAD001 10 mg/day followed by post-radiation temozolomide and post-radiation RAD001 10 mg/day.
Ph II: RT + TMZ	concurrent temozolomide	Radiation therapy and concurrent temozolomide followed by post-radiation temozolomide
Ph II: RT + TMZ	Radiation therapy	Radiation therapy and concurrent temozolomide followed by post-radiation temozolomide
Ph II: RT + TMZ	post-radiation RAD001 10 mg/day	Radiation therapy and concurrent temozolomide followed by post-radiation temozolomide
Ph II: RT + TMZ + RAD001	concurrent RAD001 10 mg/day	Radiation therapy, concurrent temozolomide, and concurrent RAD001 10 mg/day followed by post-radiation temozolomide and post-radiation RAD001 10 mg/day.
Ph II: RT + TMZ + RAD001	Radiation therapy	Radiation therapy, concurrent temozolomide, and concurrent RAD001 10 mg/day followed by post-radiation temozolomide and post-radiation RAD001 10 mg/day.
Ph II: RT + TMZ + RAD001	post-radiation RAD001 10 mg/day	Radiation therapy, concurrent temozolomide, and concurrent RAD001 10 mg/day followed by post-radiation temozolomide and post-radiation RAD001 10 mg/day.
Ph II: RT + TMZ + RAD001	post-radiation temozolomide	Radiation therapy, concurrent temozolomide, and concurrent RAD001 10 mg/day followed by post-radiation temozolomide and post-radiation RAD001 10 mg/day.
Ph I: RT + TMZ + RAD001 2.5 mg/day	concurrent temozolomide	Radiation therapy (RT), concurrent temozolomide (TMZ), and concurrent RAD001 2.5 mg/day followed by post-radiation temozolomide and post-radiation RAD001 10 mg/day.
Ph I: RT + TMZ + RAD001 2.5 mg/day	post-radiation temozolomide	Radiation therapy (RT), concurrent temozolomide (TMZ), and concurrent RAD001 2.5 mg/day followed by post-radiation temozolomide and post-radiation RAD001 10 mg/day.
Ph I: RT + TMZ + RAD001 5 mg/day	concurrent temozolomide	Radiation therapy, concurrent temozolomide, and concurrent RAD001 5 mg/day followed by post-radiation temozolomide and post-radiation RAD001 10 mg/day.
Ph I: RT + TMZ + RAD001 5 mg/day	post-radiation temozolomide	Radiation therapy, concurrent temozolomide, and concurrent RAD001 5 mg/day followed by post-radiation temozolomide and post-radiation RAD001 10 mg/day.
Ph I: RT + TMZ + RAD001 10 mg/day	concurrent temozolomide	Radiation therapy, concurrent temozolomide, and concurrent RAD001 10 mg/day followed by post-radiation temozolomide and post-radiation RAD001 10 mg/day.
Ph I: RT + TMZ + RAD001 10 mg/day	post-radiation temozolomide	Radiation therapy, concurrent temozolomide, and concurrent RAD001 10 mg/day followed by post-radiation temozolomide and post-radiation RAD001 10 mg/day.
Ph II: RT + TMZ	post-radiation temozolomide	Radiation therapy and concurrent temozolomide followed by post-radiation temozolomide
Ph II: RT + TMZ + RAD001	concurrent temozolomide	Radiation therapy, concurrent temozolomide, and concurrent RAD001 10 mg/day followed by post-radiation temozolomide and post-radiation RAD001 10 mg/day.

Primary Outcome Measures

Name	Time	Method
Phase I: Number of Patients With Dose-limiting Toxicity (DLT)	From start of treatment to eight weeks.	DLT is defined as any of the following events occurring during the first 8 weeks of treatment with RAD001 and temozolomide and attributable to the study drugs: any grade 3 or 4 thrombocytopenia, grade 4 anemia, or grade 4 neutropenia lasting more than 7 days; any non-hematologic grade 3 or greater adverse event (AE), excluding alopecia, despite maximal medical therapy; any grade 4 radiation-induced skin changes; failure to recover from adverse events to be eligible for re-treatment with RAD001 and temozolomide within 14 days of the last dose of either drug; or any episode of non-infectious pneumonitis grade 2, 3, or 4 of any duration. Adverse events are graded using CTCAE v4.0. Grade refers to the severity of the AE. The CTCAE v4.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE
Phase II: Progression-free Survival (PFS)	Analysis occured after 134 events (progression or death) were reported. Patients were followed from randomization to death or study termination whichever occurs first, up to 36.7 months.	Using the Response Assessment in Neuro- Oncology (RANO) criteria, the progression is defined by any of the following: \> 25% increase in sum of the products of perpendicular diameters of enhancing lesions compared to the smallest tumor measurement obtained either at baseline (if no decrease) or best response, on stable or increasing doses of corticosteroids; Significant increase in T2/FLAIR non-enhancing lesion on stable or increasing doses of corticosteroids compared to baseline scan or best response following initiation of therapy, not due to co-morbid events; Any new lesion; Clear clinical deterioration not attributable to other causes apart from the tumor or changes in corticosteroid dose; Failure to return for evaluation due to death or deteriorating condition; Clear progression of non-measurable disease. PFS time is defined as time from registration to date of progression, death, or last known follow-up (censored). PFS rates are estimated using the Kaplan-Meier method.

Secondary Outcome Measures

Name	Time	Method
Phase II: Overall Survival (OS)	Analysis occured after 134 events (progression or death) were reported. Patients were followed from randomization to death or study termination whichever occurs first, up to 36.7 months.	Overall survival time is defined as time from/randomization to the date of death from any cause and is estimated by the Kaplan-Meier method. Patients last known to be alive are censored at the date of last contact.
Phase I: Distribution of Worst Adverse Event Grade	Analysis occured after 134 events (progression or death) were reported. Patients were followed from randomization to death or study termination whichever occurs first, up to 36.7 months.	AE reporting in Phase I was split up by treatment timing: concurrent treatment (RT, TMZ, RAD001); post-RT treatment (TMZ, RAD001) along with all AE's reported in follow-up. The worst/highest grade of any adverse event reported in each time period was determined for each patient. The percentage of patients in each grade level is reported. Adverse events are graded using CTCAE v4.0. Grade refers to the severity of the AE. The CTCAE v4.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE.
Phase II: Distribution of Worst Adverse Event Grade	Analysis occured after 134 events (progression or death) were reported. Patients were followed from randomization to death or study termination whichever occurs first, up to 36.7 months.	The worst/highest grade of any adverse event reported was determined for each patient. The percentage of patients in each grade level is reported. Adverse events are graded using CTCAE v4.0. Grade refers to the severity of the AE. The CTCAE v4.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE.

Trial Locations

Locations (36): St. Barnabas Medical Center Cancer Center
🇺🇸
Livingston, New Jersey, United States
Winship Cancer Institute of Emory University
🇺🇸
Atlanta, Georgia, United States
St. Agnes Hospital Cancer Center
🇺🇸
Baltimore, Maryland, United States
St. Vincent Oncology Center
🇺🇸
Indianapolis, Indiana, United States
Dana-Farber/Brigham and Women's Cancer Center
🇺🇸
Boston, Massachusetts, United States
University of Texas Health Science Center at San Antonio
🇺🇸
San Antonio, Texas, United States
Flagler Cancer Center
🇺🇸
Saint Augustine, Florida, United States
Summa Center for Cancer Care at Akron City Hospital
🇺🇸
Akron, Ohio, United States
Regional Cancer Center at Singing River Hospital
🇺🇸
Pascagoula, Mississippi, United States
Rhode Island Hospital Comprehensive Cancer Center
🇺🇸
Providence, Rhode Island, United States
Huntsman Cancer Institute at University of Utah
🇺🇸
Salt Lake City, Utah, United States
Medical College of Wisconsin Cancer Center
🇺🇸
Milwaukee, Wisconsin, United States
CCOP - Christiana Care Health Services
🇺🇸
Newark, Delaware, United States
University of Florida Shands Cancer Center
🇺🇸
Gainesville, Florida, United States
Baptist Cancer Institute - Jacksonville
🇺🇸
Jacksonville, Florida, United States
Integrated Community Oncology Network
🇺🇸
Jacksonville Beach, Florida, United States
Integrated Community Oncology Network at Southside Cancer Center
🇺🇸
Jacksonville, Florida, United States
Baptist Medical Center South
🇺🇸
Jacksonville, Florida, United States
Integrated Community Oncology Network - Orange Park
🇺🇸
Orange Park, Florida, United States
Florida Cancer Center - Palatka
🇺🇸
Palatka, Florida, United States
H. Lee Moffitt Cancer Center and Research Institute at University of South Florida
🇺🇸
Tampa, Florida, United States
University Radiation Oncology at Parkridge Hospital
🇺🇸
Rochester, New York, United States
New York Oncology Hematology, PC at Albany Regional Cancer Care
🇺🇸
Albany, New York, United States
Blumenthal Cancer Center at Carolinas Medical Center
🇺🇸
Charlotte, North Carolina, United States
James P. Wilmot Cancer Center at University of Rochester Medical Center
🇺🇸
Rochester, New York, United States
Barberton Citizens Hospital
🇺🇸
Barberton, Ohio, United States
Cleveland Clinic Taussig Cancer Center
🇺🇸
Cleveland, Ohio, United States
Willamette Valley Cancer Center - Eugene
🇺🇸
Eugene, Oregon, United States
Cherry Tree Cancer Center
🇺🇸
Hanover, Pennsylvania, United States
McGlinn Family Regional Cancer Center at Reading Hospital and Medical Center
🇺🇸
Reading, Pennsylvania, United States
York Cancer Center at Apple Hill Medical Center
🇺🇸
York, Pennsylvania, United States
Waukesha Memorial Hospital Regional Cancer Center
🇺🇸
Waukesha, Wisconsin, United States
Tel-Aviv Sourasky Medical Center
🇮🇱
Tel Aviv, Israel
Ottawa Hospital Regional Cancer Centre - General Campus
🇨🇦
Ottawa, Ontario, Canada
Adams Cancer Center
🇺🇸
Gettysburg, Pennsylvania, United States
Tyler Cancer Center
🇺🇸
Tyler, Texas, United States