Imatinib Mesylate, Vatalanib, and Hydroxyurea in Treating Patients With Recurrent or Relapsed Malignant Glioma

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

Detailed Description
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OBJECTIVES: Determine the maximum tolerated dose and dose-limiting toxicity of imatinib mesylate and vatalanib when administered with hydroxyurea in patients with recurrent or relapsed grade 3 or 4 malignant glioma. Determine the safety and tolerability of this regimen in these patients. Determine the single-dose and repeated-dose pharmacokinetic profiles of imatinib mesylate (in serum) and vatalanib in these patients. Determine the pre- and post-treatment antiangiogenic effects of this regimen in these patients, using dynamic contrast-enhanced MRI to evaluate changes in the extent of vascular permeability, perfusion, and relative tumor blood volume. Determine whether changes in diffusion-weighted images MRI (quantitated by apparent diffusion coefficient maps) correlate with tumor cellularity and tumor cell death in patients treated with this regimen. Determine antitumor activity of this regimen, in terms of radiographic response, progression-free survival, and overall survival, in these patients. OUTLINE: This is an open-label, dose-escalation study of imatinib mesylate and vatalanib. Patients receive oral vatalanib once daily, oral imatinib mesylate once daily, and oral hydroxyurea twice daily on days 1-28*. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. NOTE: *Patients receive vatalanib alone daily on days 1-7 followed by vatalanib, imatinib mesylate, and hydroxyurea on days 8-35 in course 1 only. Cohorts of 3-6 patients receive escalating doses of imatinib mesylate and vatalanib 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. At least 6 patients are treated at the MTD. After completion of study treatment, patients will be evaluated for 28 days. PROJECTED ACCRUAL: A total of 42 patients will be accrued for this study.

Official Title
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Phase I Dose Escalation of Gleevec in Combination With PTK787/ZK 222584 (PTK/ZK) Plus Hydroxyurea

Conditions
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Brain and Central Nervous System Tumors

Intervention / Treatment
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* Drug: hydroxyurea
* Drug: imatinib mesylate
* Drug: vatalanib


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed malignant glioma Grade 3 or 4 disease In first, second, or third recurrence or relapse Multifocal disease allowed PATIENT CHARACTERISTICS: Karnofsky performance status 70-100% Life expectancy ≥ 12 weeks Absolute neutrophil count > 1,500/mm^3 Hemoglobin > 9 g/dL Platelet count > 100,000/mm^3 Potassium normal* Total calcium (corrected) normal* Magnesium normal* Phosphorus normal* aspartate transaminase (AST) and alanine transaminase (ALT) < 2.5 times upper limit of normal (ULN) Bilirubin < 1.5 times ULN Negative proteinuria by dipstick OR total urinary protein ≤ 500 mg with creatinine clearance ≥ 50 mL/min by 24-hour urine collection Creatinine < 1.5 times ULN OR creatinine clearance > 50 mL/min Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No acute or chronic liver or renal disease left ventricular ejection fraction (LVEF) ≥ 45% by Multi Gated Acquisition Scan (MUGA) or echocardiogram No complete left bundle branch block No obligate use of a cardiac pacemaker No congenital long QT syndrome No history of or current ventricular or atrial tachyarrhythmias No clinically significant resting bradycardia (i.e., heart rate < 50 beats/minute) No right bundle branch block with left anterior hemiblock (bifascicular block) No uncontrolled hypertension ≥ grade 2, history of labile hypertension, or history of poor compliance with an antihypertensive regimen No concurrent unstable angina pectoris or angina pectoris within the past 3 months No congestive heart failure (CHF) No history of CHF or arrhythmias requiring concurrent digoxin or verapamil No acute myocardial infarction within the past 3 months No other impaired cardiac function or clinically significant cardiac disease No peripheral neuropathy ≥ grade 2 No unresolved diarrhea ≥ grade 2 No uncontrolled diabetes No active or uncontrolled infection requiring intravenous antibiotics No impaired gastrointestinal (GI) function or GI disease that may significantly alter the absorption of vatalanib, hydroxyurea, and/or everolimus, including any of the following: Ulcerative disease Uncontrolled nausea, vomiting, or diarrhea Malabsorption syndrome Small bowel resection No other concurrent severe and/or uncontrolled medical condition that would preclude study participation or compliance No known HIV positivity No other primary malignancy that is clinically significant or requires active intervention NOTE: *Supplement allowed PRIOR CONCURRENT THERAPY: See Disease Characteristics More than 2 weeks since prior tumor biopsy (4 weeks since prior surgical resection) Prior polifeprosan 20 with carmustine implant (Gliadel® wafer) allowed at discretion of principal investigator Prior hydroxyurea allowed More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas and 1 week for metronomic-dosed chemotherapy [e.g., daily etoposide hydrochloride or cyclophosphamide]) and recovered More than 4 weeks since prior radiotherapy and recovered More than 2 weeks since prior immunotherapy and recovered More than 4 weeks since prior investigational drugs and recovered No prior platelet-derived growth factor- or vascular endothelial growth factor-directed therapies More than 2 weeks since prior hematopoietic colony-stimulating factor (e.g., filgrastim [G-CSF] or sargramostim [Granulocyte-macrophage colony-stimulating factor (GM-CSF)]) Prior epoetin alfa allowed 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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Gleevec + PTK787/ZK 22584 + Hydroxyurea<br>Patients with recurrent or relapsing glioblastoma multiforme (GBM) will be given daily doses of Gleevec and PTK787/ZK 22584 orally in combination with fixed doses of hydroxyurea. | Drug: hydroxyurea<br> <br> * Other names: hydrea;Drug: imatinib mesylate<br> <br> * Other names: Gleevec;Drug: vatalanib<br> <br> * Other names: PTK787;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose and dose-limiting toxicity of imatinib mesylate and vatalanib when administered with hydroxyurea |  | 1 Year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety |  | 1.5 Years | 
| Tolerability |  | 1 Year | 
| Pharmacokinetic | To characterize the single-dose and repeated-dose pharmacokinetic (PK) profiles of imatinib mesylate (in serum) and PTK787/ZK 22584 combination therapy in this patient population. | 1.5 Years | 
| Antiangiogenic effects | pre- and post-treatment, of imatinib mesylate, PTK787/ZK 22584 and hydroxyurea combination therapy, using Dynamic contrast enhanced-magnetic resonance imaging (DCE-MRI) to evaluate changes in the extent of vascular permeability, perfusion and relative tumor blood volume; to explore assessment of tumor cellularity and tumor cell death by changes in diffusion weighted imaging magnetic resonance imaging (DWI-MRI) as quantitated by apparent diffusion coefficient maps (ADC maps). To note the anti-tumor activity of this regimen in terms of radiographic response, progression-free survival and overall survival. | 1 Year | 

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