Temozolomide and Everolimus in Treating Patients With Newly Diagnosed, Recurrent, or Progressive Malignant Glioblastoma Multiforme - Full Text View

Sponsored by:	National Cancer Institute of Canada
Information provided by:	National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:	NCT00387400

Purpose

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	Intervention	Phase
Brain and Central Nervous System Tumors	Drug: everolimus Drug: temozolomide Procedure: adjuvant therapy Procedure: gene expression profiling Procedure: immunohistochemistry staining method Procedure: pharmacological study	Phase I

MedlinePlus related topics: Cancer

Drug Information available for: Temozolomide Everolimus

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Treatment, Non-Randomized, Open Label
Official Title:	A Phase I Study of Temozolomide and RAD001C in Patients With Malignant Glioblastoma Multiforme

Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:

Safety and tolerability of everolimus as measured by NCI CTCAE v3.0 [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

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 [ Designated as safety issue: No ]
Correlation of clinical outcome with pretreatment tumor tissue molecular markers as measured by molecular studies of paraffin-embedded tumor samples [ Designated as safety issue: No ]
Pharmacokinetics of everolimus during course 1 [ Designated as safety issue: No ]

Estimated Enrollment:	30
Study Start Date:	July 2006
Estimated Primary Completion Date:	July 2009 (Final data collection date for primary outcome measure)

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.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00387400

Locations

Canada, Alberta
Cross Cancer Institute at University of Alberta	Recruiting
Edmonton, Alberta, Canada, T6G 1Z2
Contact: Dorcas Fulton 780-432-8517
Tom Baker Cancer Centre - Calgary	Recruiting
Calgary, Alberta, Canada, T2N 4N2
Contact: Jacob Easaw 403-521-3446
Canada, British Columbia
British Columbia Cancer Agency - Centre for the Southern Interior	Recruiting
Kelowna, British Columbia, Canada, V1Y 5L3
Contact: Delia Sauciuc 250-712-3900
British Columbia Cancer Agency - Vancouver Cancer Centre	Recruiting
Vancouver, British Columbia, Canada, V5Z 4E6
Contact: Brian Thiessen 604-877-6000
Canada, Nova Scotia
Nova Scotia Cancer Centre	Recruiting
Halifax, Nova Scotia, Canada, B3H 1V7
Contact: Mary MacNeil 902-473-8317
Canada, Ontario
London Regional Cancer Program at London Health Sciences Centre	Recruiting
London, Ontario, Canada, N6A 4L6
Contact: David R. MacDonald 519-685-8640
Princess Margaret Hospital	Recruiting
Toronto, Ontario, Canada, M5G 2M9
Contact: Warren Mason 416-946-2277
Canada, Quebec
Hopital Notre-Dame du CHUM	Recruiting
Montreal, Quebec, Canada, H2L 4M1
Contact: Karl Belanger 514-890-8200
McGill Cancer Centre at McGill University	Recruiting
Montreal, Quebec, Canada, H2W 1S6
Contact: Petr Kavan 514-398-1444

Sponsors and Collaborators

National Cancer Institute of Canada

Investigators

Study Chair:

Warren P. Mason, MD

Princess Margaret Hospital, Canada

More Information

Clinical trial summary from the National Cancer Institute's PDQ® database This link exits the ClinicalTrials.gov site

Study ID Numbers:	CDR0000507616, CAN-NCIC-IND162
Study First Received:	October 12, 2006
Last Updated:	January 7, 2009
ClinicalTrials.gov Identifier:	NCT00387400
Health Authority:	Unspecified

Keywords provided by National Cancer Institute (NCI):

adult giant cell glioblastoma
adult gliosarcoma
recurrent adult brain tumor
adult glioblastoma

Study placed in the following topic categories:

Everolimus
Glioblastoma
Astrocytoma
Central Nervous System Neoplasms
Temozolomide
Recurrence
Brain Neoplasms
Neuroectodermal Tumors

Glioblastoma multiforme
Neoplasms, Germ Cell and Embryonal
Neuroepithelioma
Glioma
Gliosarcoma
Nervous System Neoplasms
Neoplasms, Glandular and Epithelial

Additional relevant MeSH terms:

Neoplasms by Histologic Type
Immunologic Factors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Physiological Effects of Drugs
Neoplasms, Nerve Tissue
Nervous System Diseases
Immunosuppressive Agents

Pharmacologic Actions
Neoplasms
Neoplasms by Site
Therapeutic Uses
Antineoplastic Agents, Alkylating
Neoplasms, Neuroepithelial
Alkylating Agents

ClinicalTrials.gov processed this record on January 16, 2009