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

Sponsor

NCIC Clinical Trials Group (Other)

Overall Status

Completed

CT.gov ID

NCT00387400

Collaborator

(none)

Enrollment

Locations

65.4

Actual Duration (Months)

3.6

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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

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.

Study Design

Study Type:

Interventional

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 :

Jul 25, 2006

Actual Primary Completion Date :

Sep 24, 2010

Actual Study Completion Date :

Jan 6, 2012

Outcome Measures

Primary Outcome Measures

Safety and tolerability of everolimus as measured by NCI CTCAE v3.0 [from the time of the first treatment]

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 [after every other course]
Correlation of clinical outcome with pretreatment tumor tissue molecular markers as measured by molecular studies of paraffin-embedded tumor samples [4 years]
Assessed at study completion
Pharmacokinetics of everolimus during course 1 [during course 1]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 120 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Locations

	Site	City	State	Country	Postal Code
1	Tom Baker Cancer Centre	Calgary	Alberta	Canada	T2N 4N2
2	Cross Cancer Institute	Edmonton	Alberta	Canada	T6G 1Z2
3	BCCA - Cancer Centre for the Southern Interior	Kelowna	British Columbia	Canada	V1Y 5L3
4	BCCA - Vancouver Cancer Centre	Vancouver	British Columbia	Canada	V5Z 4E6
5	QEII Health Sciences Center	Halifax	Nova Scotia	Canada	B3H 1V7
6	London Regional Cancer Program	London	Ontario	Canada	N6A 4L6
7	Univ. Health Network-Princess Margaret Hospital	Toronto	Ontario	Canada	M5G 2M9
8	CHUM - Hopital Notre-Dame	Montreal	Quebec	Canada	H2L 4M1
9	McGill University - Dept. Oncology	Montreal	Quebec	Canada	H2W 1S6