Imatinib Mesylate in Treating Patients With Recurrent Brain Tumor

Study Overview
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Brief Summary
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This phase I/II trial is studying the side effects and best dose of imatinib mesylate and to see how well it works in treating patients with a recurrent brain tumor that has not responded to previous surgery and radiation therapy. Imatinib mesylate may stop the growth of tumor cells by blocking the enzymes necessary for tumor cell growth.

Detailed Description
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PRIMARY OBJECTIVES: I. To identify the maximum tolerated dose of imatinib (imatinib mesylate) in patients with recurrent oligodendroglioma and mixed oligoastrocytoma that are currently on enzyme inducing anticonvulsant therapy. (Study 1) II. To assess the efficacy of imatinib in patients with recurrent oligodendrogliomas and mixed oligoastrocytomas (with pathologic evidence of oligodendrogliomatous component) as measured by progression-free survival, response, and overall survival. (Study 2) III. To acquire pilot data on a patient group not traditionally eligible for recurrent oligodendroglioma and mixed oligoastrocytoma clinical trials (those having > 2 prior chemotherapy regimens or 2 prior chemotherapy regimens for recurrent/progressive disease). (Study 3) IV. To examine the toxicity and safety of imatinib in patients with recurrent oligodendrogliomas and mixed oligoastrocytomas (with pathologic evidence of oligodendrogliomatous component). (Studies 1, 2, and 3) V. To perform a preliminary correlative study of 1p/19q alterations, alpha platelet-derived growth factor receptor (PDFGR) gene amplification and levels of related downstream signaling elements in tumor tissue, with clinical study endpoints. (Studies 1, 2, and 3) VI. To perform a descriptive correlative analysis of steady state pharmacokinetic data regarding imatinib and active metabolites with the study endpoints. (Studies 1, 2, and 3) OUTLINE: This is a phase I, dose-escalation study followed by a phase II and a pilot study.

Official Title
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Phase I/II Trial of Imatinib Mesylate; (Gleevec; STI571) in Treatment of Recurrent Oligodendroglioma and Mixed Oligoastrocytoma

Conditions
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Adult Anaplastic Oligodendroglioma, Adult Mixed Glioma, Adult Oligodendroglioma, Recurrent Adult Brain Neoplasm

Intervention / Treatment
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* Drug: Imatinib Mesylate
* Other: Laboratory Biomarker Analysis
* Other: Pharmacological Study


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Study 1 Arm C: Currently on anticonvulsants which can induce cytochrome p450 (phenytoin, carbamazepine, barbiturates, primidone and if unsure contact study chair) =< 2 prior chemotherapy regimens (with maximum of 1 prior chemotherapy regimen for recurrent disease) Study 2 Arms A and B: On or off anticonvulsants =< 2 prior chemotherapy regimens (with maximum of 1 prior chemotherapy regimen for recurrent disease) Study 3 Arms D and E: On or off anticonvulsants > 2 chemotherapy regimens or 2 prior chemotherapy regimens for progressive/recurrent disease All Arms: Histological confirmation of a grade 2-4 oligodendroglioma, or mixed oligoastrocytoma grade 2-4 containing oligodendrogliomatous component on central pathology review prior to study registration, and a diagnosis of recurrence; tissues from all available prior surgeries should be sent, in particular those from time of initial diagnosis Measurable or evaluable disease by magnetic resonance imaging (MRI) or computed tomography (CT) scan Fixed dose of corticosteroids (or no corticosteroids) for at least 1 week prior to the pre-study baseline scan Patients undergoing surgery for initial or progressive disease, must be at least 2 weeks from the date of surgery, must have recovered from the effects of their surgery, and must have unequivocal tumor growth on the pre-study baseline neuroimaging study as compared to the first post-operative scan, unless there is a separate lesion or residual disease compatible with tumor that is not within the surgical bed Unequivocal evidence of tumor progression by MRI or CT scan performed =< 21days prior to study registration Must have failed surgery/radiotherapy (RT) and Temozolomide or nitrosourea based therapy >= 12 weeks since the completion of RT Absolute neutrophil count (ANC) >= 1500/mm^3 Platelets (PLT) >= 100,000/mm^3 Hemoglobin (Hgb) >= 9 g/dL Total bilirubin =< 1.5 mg/dL Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) =< 3 x upper limit of normal (ULN) Creatinine =< 2.0 mg/dL Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1, or 2 >= 6 weeks since the last day of nitrosourea-based chemotherapy prior to study entry >= 4 weeks from any investigational agents prior to study entry >= 4 weeks from other chemotherapy prior to study entry >= 2 weeks from vincristine and biologic non-cytotoxic agents, e.g., tamoxifen, thalidomide, cis-retinoic acid, interferon, etc, prior to study entry Patients or designated individual(s) with durable medical power of attorney for the patient must be able to provide informed, written consent, and complete any required study questionnaire(s) within the specifications of this study Exclusion Criteria: All Arms Receiving warfarin or heparin Received prior stereotactic radiosurgery, interstitial brachytherapy, or interstitial chemotherapy including carmustine (BCNU) wafers unless there is a separate lesion on MRI, which is not part of the previous treatment field Active uncontrolled infection History of myocardial infarction =< 6 months or congestive heart failure (CHF) requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias; patients must have a New York Heart Association (NYHA) of class II or less; (NYHA class I: patients with no limitation of activities; they suffer no symptoms from ordinary activities; class II: patients with slight, mild limitation of activity; they are comfortable with rest or with mild exertion; class III: patients with marked limitation of activity; they are comfortable only at rest; class IV: patients who should be at complete rest, confined to bed or chair; any physical activity brings on discomfort and symptoms occur at rest) Other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the interpretation of potential drug-induced toxicities Women of child-bearing potential, pregnant or nursing; such patients must have a negative pregnancy test (b-HCG) =< 7 days prior to study registration Men or women of childbearing potential, not willing to employ adequate contraception (condoms, diaphragm, birth control pills, injections, intrauterine device [IUD], surgical sterilization, subcutaneous implants, or abstinence, etc.); the efficacy of oral contraceptives may be decreased in patients who receive p450-inducing anticonvulsants; for these patients, use of a second mode of contraception is recommended; patients of childbearing potential must utilize effective contraception and avoid becoming pregnant or fathering a child for 6 months after completing study drug Other active malignancy, besides skin carcinomas (must not be melanoma) Concomitant serious immunocompromised status (other than that related to concomitant steroids); patients that are human immunodeficiency virus (HIV) positive are eligible, provided that there is no other reason for exclusion, based on the eligibility as outlined elsewhere in this section Significant intratumoral hemorrhage on baseline MRI or CT, or other history of significant intratumoral hemorrhage

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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase II (Group 1)<br>Patients receive imatinib mesylate PO, at the MTD determined in phase I, BID for 4 weeks. | Drug: Imatinib Mesylate<br>* Given PO<br>* Other names: STI571;Other: Laboratory Biomarker Analysis<br>* Optional correlative studies<br>Other: Pharmacological Study<br>* Optional correlative studies<br>|
| Experimental: Phase II (Group 2)<br>Patients receive standard-dose imatinib mesylate PO BID for 4 weeks. | Drug: Imatinib Mesylate<br>* Given PO<br>* Other names: STI571;Other: Laboratory Biomarker Analysis<br>* Optional correlative studies<br>Other: Pharmacological Study<br>* Optional correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 6-month Progression-free Survival (PFS), Defined as a Patient Being Alive and Progression-free 183 Days After the Date of Registration. | The proportion of successes will be estimated using the Binomial point estimator (number of successes divided by the total number of evaluable patients) and the Binomial 90% confidence interval estimated using the Duffy-Santer algorithm. Progression is defined using response criteria (the neurologic examination and the MRI and/or CT), >25% increase in product of perpendicular diameters of contrast enhancement or mass or appearance of new lesions. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Confirmed Response (i.e., an Objective Status of Complete Response (CR), Partial Response (PR), or Regression (REGR) on 2 Successive Evaluations at Least 4 Weeks Apart After the Start of Study Treatment). | Complete Response (CR) is defined using response criteria (the neurologic examination and the Magnetic resonance imaging (MRI) and/or Computerized Tomography (CT)), total disappearance of all tumor with patient off corticosteroids or only on adrenal replacement maintenance. Partial Response (PR) is defined using response criteria (the neurologic examination and the MRI and/or CT), >=50% reduction in product of perpendicular diameters of contrast enhancement or mass with no new lesions with the patient being on stable or decreased steroid dose. Regression (REGR) is defined using response criteria (the neurologic examination and the MRI and/or CT), unequivocal reduction in size of contrast-enhancement or decrease in mass effect as agreed upon independently by primary physician and quality control physicians; no new lesions. Patient should be on stable or decreased steroid dose. | Up to 5 years | 
| Percentage of Patients Progression-free | The percentage of patient progression-free at 12 months, 18 months, and PFS will be estimated. Kaplan-Meier survival curves and logrank tests will be used to estimate progression-time distributions. Progression is defined using response criteria (the neurologic examination and the MRI and/or CT), >25% increase in product of perpendicular diameters of contrast enhancement or mass or appearance of new lesions. | Time from study registration to date of disease progression or last follow-up, assessed up to 5 years | 
| Overall Time to Death | Kaplan-Meier survival curves and logrank tests will be used to estimate survival distributions. | Time from date of registration to date of death due to any cause or last follow-up, assessed up to 5 years |