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A Phase I Study of Temozolomide and RAD001C in Patients With Malignant Glioblastoma Multiforme

Phase 1
18 Years
Not Enrolling
Brain and Central Nervous System Tumors

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Trial Information

A Phase I Study of Temozolomide and RAD001C in Patients With Malignant Glioblastoma Multiforme



- 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.

Inclusion Criteria


- 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

- 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


- 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

- No concurrent grapefruit juice

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Safety and tolerability of everolimus as measured by NCI CTCAE v3.0

Outcome Time Frame:

from the time of the first treatment

Safety Issue:


Principal Investigator

Warren P. Mason, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Princess Margaret Hospital, Canada


Canada: Health Canada

Study ID:




Start Date:

July 2006

Completion Date:

January 2012

Related Keywords:

  • Brain and Central Nervous System Tumors
  • adult giant cell glioblastoma
  • adult gliosarcoma
  • recurrent adult brain tumor
  • adult glioblastoma
  • Glioblastoma
  • Nervous System Neoplasms
  • Central Nervous System Neoplasms