Clinical Trial Finder

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

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.

Arms

Experimental: Gleevec + PTK787/ZK 22584 + Hydroxyurea

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.

Interventions

Drug: - hydroxyurea

Drug: - imatinib mesylate

Drug: - vatalanib