Temozolomide + Everolimus in Newly Diagnosed, Recurrent, or Progressive Malignant Glioblastoma Multiforme
Condition: Brain and Central Nervous System Tumors
MeSH terms: Glioblastoma; Nervous System Neoplasms; Central Nervous System Neoplasms
Study type: Interventional
Phase: Phase 1

Summary: 
      RATIONALE: 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.
      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. Giving temozolomide together with everolimus
      may kill more tumor cells.

      PURPOSE: This phase I trial is studying the side effects and best dose of everolimus when
      given together with temozolomide in treating patients with newly diagnosed, recurrent, or
      progressive malignant glioblastoma multiforme.
    

Detailed description: 
      OBJECTIVES:

      Primary

        -  Determine the maximum tolerated dose(s) and the recommended phase II dose(s) of
           everolimus when administered with standard-dose temozolomide in patients with newly
           diagnosed, recurrent, or progressive glioblastoma multiforme.

        -  Determine the toxicity of this regimen in these patients.

      Secondary

        -  Determine the efficacy of this regimen in patients with measurable disease at baseline.

        -  Identify correlates of activity by molecular study of paraffin-embedded tumor samples
           from these patients.

        -  Determine the pharmacokinetics of this regimen in these patients.

      OUTLINE: This is a nonrandomized, nonblinded, parallel-group, multicenter, dose-escalation
      study of everolimus. Patients are stratified according to concurrent use of enzyme-inducing
      antiepileptic drugs (yes vs no).

      Patients receive oral temozolomide once daily on days 2-5 in course 1 and on days 1-5 in all
      subsequent courses. Patients also receive oral everolimus once daily on days 1-28. Treatment
      repeats every 4 weeks in the absence of disease progression or unacceptable toxicity.
      Patients with newly diagnosed disease receive up to 6 courses of treatment. Patients with
      recurrent disease who achieve a response (partial or complete response) or stable disease may
      continue treatment until disease progression or unacceptable toxicity.

      Cohorts of 3-6 patients per stratum receive escalating doses of everolimus until the maximum
      tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2
      of 3 or 2 of 6 patients experience dose-limiting toxicity during the first course of therapy.
      Once the MTD is determined, an additional 6 patients are treated at the MTD.

      Patients' archival diagnostic tumor tissue is evaluated during study for correlative
      molecular studies (by immunohistochemical staining) of mammalian target of rapamycin
      inhibition status (mTOR activity) and pretreatment molecular markers. Blood samples are taken
      periodically during course 1 for pharmacokinetic studies.

      After completion of study therapy, patients are followed at 4 weeks. Patients with stable or
      responding disease are then followed every 3 months until relapse or progression.

      PROJECTED ACCRUAL: A total of 30 patients will be accrued for this study.
    

Intervention name(s): everolimus; temozolomide; microarray analysis; immunohistochemistry staining method
Intervention type(s): Drug; Drug; Genetic; Other
Intervention description(s): 150 mg/m2/day PO Daily x 5, q 4 weeks; 2.5 mg PO Daily, beginning day 2 of cycle 1, q 4 weeks; Tissue sections will be stained by immunohisto-chemistry using the following antibodies: EGFRvIII, PTEN, phospho-specific PKB/Akt Ser473; phosphor-mTORSer2448, p70S6K Thr389; S6 ribosomal protein Ser235/236. These antibodies are selected on the basis of providing a readout of upstream and downstream signaling through mTOR, and availability of antibodies that reliably stain paraffinembedded tissue.; Tissue sections will be stained by immunohisto-chemistry using the following antibodies: EGFRvIII, PTEN, phospho-specific PKB/Akt Ser473; phosphor-mTORSer2448, p70S6K Thr389; S6 ribosomal protein Ser235/236. These antibodies are selected on the basis of providing a readout of upstream and downstream signaling through mTOR, and availability of antibodies that reliably stain paraffinembedded tissue.
Intervention MeSH terms: Everolimus; Temozolomide
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: adult giant cell glioblastoma; adult gliosarcoma; recurrent adult brain tumor; adult glioblastoma