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

NCIC Clinical Trials Group

Status and phase

Completed

Phase 1

Conditions

Brain and Central Nervous System Tumors

Treatments

Drug: everolimus

Other: immunohistochemistry staining method

Drug: temozolomide

Genetic: microarray analysis

Study type

Interventional

Funder types

NETWORK

Identifiers

NCT00387400

CAN-NCIC-IND162 (Registry Identifier)

I162

CDR0000507616 (Other Identifier)

Details and patient eligibility

About

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.

Full 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.

Enrollment

32 patients

Sex

All

Ages

18 to 120 years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion criteria

DISEASE CHARACTERISTICS:

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

PATIENT CHARACTERISTICS:

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

PRIOR CONCURRENT THERAPY:

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