Conditions: Brain and Central Nervous System Tumors
Keywords: adult glioblastoma adult giant cell glioblastoma adult gliosarcoma
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 279
Healthy volunteers: no

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.

Arms:
arm 1: 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. arm 2: Radiation therapy, concurrent temozolomide, and concurrent RAD001 5 mg/day followed by post-radiation temozolomide and post-radiation RAD001 10 mg/day. arm 3: Radiation therapy, concurrent temozolomide, and concurrent RAD001 10 mg/day followed by post-radiation temozolomide and post-radiation RAD001 10 mg/day. arm 4: Radiation therapy and concurrent temozolomide followed by post-radiation temozolomide arm 5: Radiation therapy, concurrent temozolomide, and concurrent RAD001 10 mg/day followed by post-radiation temozolomide and post-radiation RAD001 10 mg/day.

Interventions: intervention 1: concurrent RAD001 10 mg/day intervention 2: concurrent temozolomide intervention 3: Radiation therapy intervention 4: concurrent RAD001 2.5 mg/day intervention 5: concurrent RAD001 5 mg/day intervention 6: post-radiation RAD001 10 mg/day intervention 7: post-radiation temozolomide
Intervention descriptions: intervention 1: During radiation: RAD001 10 mg orally daily during radiation therapy; one hour prior to radiation and in the morning on weekends on days 1-42. intervention 2: During radiation: temozolomide 75 mg/m2/day orally daily during radiation therapy; one hour prior to radiation and in the morning on weekends on days 1-42. Dose rounded to the nearest 5 mg. intervention 3: Intensity Modulated RT (IMRT) allowed. For both IMRT and 3D conformal radiotherapy (3D-CRT) plans, one treatment of 2 Gy given daily 5 days per week for a total of 60 Gy over 6 weeks. intervention 4: During radiation: RAD001 2.5 mg orally daily during radiation therapy; one hour prior to radiation and in the morning on weekends on days 1-42. intervention 5: During radiation: RAD001 5 mg orally daily during radiation therapy; one hour prior to radiation and in the morning on weekends on days 1-42. intervention 6: Post-radiation: RAD001 10 mg orally daily on days 1-28 of each cycle, for up to 12 cycles, starting 28 days after the completion of radiation therapy (Cycle = 28 days). intervention 7: Post-radiation: temozolomide 150 mg/m2/day - 200 mg/m2/day orally daily on days 1-5 of each cycle, starting 28 days after the completion of radiation therapy for up to 12 cycles (Cycle = 28 days)

Protocol document: