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Temozolomide + Everolimus in Newly Diagnosed, Recurrent, or Progressive Malignant Glioblastoma Multiforme

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00387400
Recruitment Status : Completed
First Posted : October 13, 2006
Last Update Posted : April 8, 2020
Information provided by (Responsible Party):
Canadian Cancer Trials Group ( NCIC Clinical Trials Group )

Brief 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.

Condition or disease Intervention/treatment Phase
Brain and Central Nervous System Tumors Drug: everolimus Drug: temozolomide Genetic: microarray analysis Other: immunohistochemistry staining method Phase 1

Detailed Description:



  • 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.


  • 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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 32 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Study of Temozolomide and RAD001C in Patients With Malignant Glioblastoma Multiforme
Actual Study Start Date : July 25, 2006
Actual Primary Completion Date : September 24, 2010
Actual Study Completion Date : January 6, 2012

Intervention Details:
  • Drug: everolimus
    150 mg/m2/day PO Daily x 5, q 4 weeks
  • Drug: temozolomide
    2.5 mg PO Daily, beginning day 2 of cycle 1, q 4 weeks
  • Genetic: microarray analysis
    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.
  • Other: immunohistochemistry staining method
    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.

Primary Outcome Measures :
  1. Safety and tolerability of everolimus as measured by NCI CTCAE v3.0 [ Time Frame: from the time of the first treatment ]

Secondary Outcome Measures :
  1. Response as measured by CT scan and/or brain MRI at baseline and after every other course and clinical neurologic assessment at baseline and after every course [ Time Frame: after every other course ]
  2. Correlation of clinical outcome with pretreatment tumor tissue molecular markers as measured by molecular studies of paraffin-embedded tumor samples [ Time Frame: 4 years ]
    Assessed at study completion

  3. Pharmacokinetics of everolimus during course 1 [ Time Frame: during course 1 ]

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years to 120 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No


  • Histologically confirmed malignant glioblastoma multiforme, meeting 1 of the following criteria:

    • Newly diagnosed disease AND meets the following criteria:

      • Has undergone prior surgery and radiotherapy with concurrent temozolomide
      • No prior chemotherapy except for concurrent low-dose temozolomide given with radiotherapy
    • Recurrent or progressive disease after front-line therapy AND meets the following criteria:

      • No more than 1 prior chemotherapy regimen in the adjuvant setting
      • More than 4 months since last adjuvant treatment
      • No prior chemotherapy for recurrence
  • Bidimensionally measurable disease, defined as ≥ 1 enhancing lesion ≥ 1 cm x 1 cm by CT scan or MRI, within 21 days of study entry (for patients with recurrent/relapsed disease)

    • Patients receiving steroids must be on stable dose for at least 14 days before baseline CT scan or MRI
  • Paraffin-embedded sample of primary or metastatic tumor diagnostic specimen must be available


  • ECOG performance status 0-2
  • Life expectancy ≥ 12 weeks
  • Absolute granulocyte count ≥ 1,500/mm³
  • Platelet count ≥ 120,000/mm³
  • Bilirubin normal
  • AST and ALT ≤ 2.5 times upper limit of normal
  • Creatinine normal OR creatinine clearance ≥ 60 mL/min
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception
  • No upper gastrointestinal condition or other condition that would preclude compliance with oral medication
  • No other prior malignancy except for adequately treated nonmelanoma skin cancer, curatively treated in situ cervical cancer, or other solid tumors curatively treated with no evidence of disease for the past 5 years
  • No serious illness or underlying medical condition that would preclude study compliance, including any of the following:

    • Significant neurologic or psychiatric disorder that would preclude obtaining informed consent
    • Active, ongoing infection
  • No known hypersensitivity to everolimus or temozolomide or their components


  • See Disease Characteristics
  • At least 2 weeks since prior surgery and recovered
  • At least 4 weeks since prior radiotherapy
  • Concurrent enzyme-inducing antiepileptic drugs allowed
  • No concurrent inhibitors of cytochrome 3A4 (e.g., ketoconazole and similar antifungals, erythromycin, or diltiazem)
  • No other concurrent experimental drugs, anticancer treatment, or investigational therapy
  • No concurrent grapefruit juice

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00387400

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Canada, Alberta
Tom Baker Cancer Centre
Calgary, Alberta, Canada, T2N 4N2
Cross Cancer Institute
Edmonton, Alberta, Canada, T6G 1Z2
Canada, British Columbia
BCCA - Cancer Centre for the Southern Interior
Kelowna, British Columbia, Canada, V1Y 5L3
BCCA - Vancouver Cancer Centre
Vancouver, British Columbia, Canada, V5Z 4E6
Canada, Nova Scotia
QEII Health Sciences Center
Halifax, Nova Scotia, Canada, B3H 1V7
Canada, Ontario
London Regional Cancer Program
London, Ontario, Canada, N6A 4L6
Univ. Health Network-Princess Margaret Hospital
Toronto, Ontario, Canada, M5G 2M9
Canada, Quebec
CHUM - Hopital Notre-Dame
Montreal, Quebec, Canada, H2L 4M1
McGill University - Dept. Oncology
Montreal, Quebec, Canada, H2W 1S6
Sponsors and Collaborators
NCIC Clinical Trials Group
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Study Chair: Warren P. Mason, MD Princess Margaret Hospital, Canada
Publications of Results:
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Responsible Party: NCIC Clinical Trials Group Identifier: NCT00387400    
Other Study ID Numbers: I162
CAN-NCIC-IND162 ( Registry Identifier: PDQ )
CDR0000507616 ( Other Identifier: PDQ )
First Posted: October 13, 2006    Key Record Dates
Last Update Posted: April 8, 2020
Last Verified: April 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Canadian Cancer Trials Group ( NCIC Clinical Trials Group ):
adult giant cell glioblastoma
adult gliosarcoma
recurrent adult brain tumor
adult glioblastoma
Additional relevant MeSH terms:
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Nervous System Neoplasms
Central Nervous System Neoplasms
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Neoplasms by Site
Nervous System Diseases
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action