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

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.

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