Imatinib Mesylate and Temozolomide in Treating Patients With Malignant Glioma

Study Overview
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Brief Summary
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RATIONALE: Imatinib mesylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. 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. Giving imatinib mesylate together with temozolomide may kill more tumor cells. PURPOSE: This phase I trial is studying the side effects and best dose of imatinib mesylate when given together with temozolomide in treating patients with malignant glioma.

Detailed Description
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OBJECTIVES: Determine the maximum tolerated dose and dose-limiting toxicity, if attainable, of imatinib mesylate in combination with temozolomide in patients with malignant glioma. Characterize the safety and tolerability of imatinib mesylate, including acute and chronic toxicities, in these patients. Determine the effect of temozolomide on the pharmacokinetics (PK) of imatinib mesylate at each dose level. Evaluate the impact of enzyme-inducing anti-epileptic drug (EIAED) coadministration on the PK of imatinib mesylate using a population-based PK approach. Evaluate the antitumor activity of imatinib mesylate plus temozolomide. OUTLINE: This is a dose-escalation study of imatinib mesylate. Patients are stratified according to concurrent enzyme-inducing anticonvulsants (e.g., phenytoin, phenobarbital, carbamazepine, fosphenytoin, primidone, oxcarbazepine) (yes vs no). Patients receive oral imatinib mesylate once or twice daily on days 1-8 and oral temozolomide once daily on days 4-8. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of patients receive escalating doses of imatinib mesylate until the maximum tolerated dose is determined. On days 1 and 8 of course 1, blood is drawn for pharmacokinetic studies. PROJECTED ACCRUAL: A total of 40 patients will be accrued for this study.

Official Title
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A Phase I Study of Imatinib Mesylate in Combination With Temozolomide in Patients With Malignant Glioma

Conditions
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Brain and Central Nervous System Tumors

Intervention / Treatment
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* Drug: imatinib mesylate
* Drug: temozolomide
* Other: pharmacological study


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed malignant glioma Any of the following subtypes: Glioblastoma multiforme Gliosarcoma Anaplastic astrocytoma Anaplastic oligodendroglioma Anaplastic oligoastrocytoma Previous histologic diagnosis of a lower grade of glioma allowed if there is histologic evidence of progression to a diagnosis of malignant glioma Multifocal disease allowed Must have undergone prior conventional external-beam radiation therapy Stable disease, disease recurrence, or relapsed disease Must not have received any systemic therapy for this recurrence or relapse No prior progressive disease No central/systemic fluid collections (pericardial effusion, pulmonary effusion, ascites) ≥ grade 2 No evidence of intratumor hemorrhage on pretreatment diagnostic imaging, except for stable post-operative grade 1 hemorrhage PATIENT CHARACTERISTICS: Karnofsky performance status 70-100% Absolute neutrophil count > 1,500/mm³ Hemoglobin > 9 g/dL Platelet count > 100,000/mm³ AST and ALT < 2.5 times upper limit of normal (ULN) Bilirubin < 1.5 times ULN Creatinine < 1.5 times ULN No chronic renal disease No active uncontrolled infection No uncontrolled diabetes No excessive risk of bleeding, as defined by occurrence of any of the following: Stroke within the past 6 months History of CNS or intraocular bleed Septic endocarditis No history of labile hypertension No congestive heart failure No poorly controlled hypertension No myocardial infarction within the past 6 months No history of poor compliance with antihypertensive regimen No other severe and/or uncontrolled medical disease that would preclude study participation No peripheral edema ≥ grade 2 No gastrointestinal bleeding No gross hematuria No other active systemic bleeding Patients must not have experienced toxicity ≥ grade 3 with prior treatment with either temozolomide or imatinib mesylate No other primary malignancy within the past 5 years except basal cell skin cancer or carcinoma in situ of the cervix or other cancer not currently clinically significant nor requiring active interventions PRIOR CONCURRENT THERAPY: See Disease Characteristics Recovered from all prior therapy Prior surgical resection(s) allowed At least 2 weeks since prior surgery At least 2 weeks since prior chemotherapy (6 weeks for nitrosoureas) At least 2 weeks since prior external-beam radiotherapy At least 2 weeks since prior investigational drugs More than 1 week since prior biologic, immunotherapeutic, or cytostatic agents No concurrent warfarin

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: imatinib mesylate|nan|
|Drug: temozolomide|nan|
|Other: pharmacological study|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose |  |  | 
| Dose-limiting toxicity |  |  | 
| Safety and tolerability |  |  | 
| Pharmacokinetics |  |  | 
| Anti-tumor activity |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adult anaplastic oligodendroglioma, adult giant cell glioblastoma, adult gliosarcoma, adult mixed glioma, adult anaplastic astrocytoma, recurrent adult brain tumor, adult glioblastoma