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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00387933
Recruitment Status : Completed
First Posted : October 13, 2006
Last Update Posted : October 14, 2015
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Duke University

Brief Summary:

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.

Condition or disease Intervention/treatment Phase
Brain and Central Nervous System Tumors Drug: hydroxyurea Drug: imatinib mesylate Drug: vatalanib Phase 1

Detailed Description:


  • 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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 37 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I Dose Escalation of Gleevec in Combination With PTK787/ZK 222584 (PTK/ZK) Plus Hydroxyurea
Study Start Date : July 2005
Actual Primary Completion Date : January 2009

Arm Intervention/treatment
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.
Drug: hydroxyurea
Other Names:
  • HU
  • hydrea

Drug: imatinib mesylate
Other Name: Gleevec

Drug: vatalanib
Other Name: PTK787

Primary Outcome Measures :
  1. Maximum tolerated dose and dose-limiting toxicity of imatinib mesylate and vatalanib when administered with hydroxyurea [ Time Frame: 1 Year ]

Secondary Outcome Measures :
  1. Safety [ Time Frame: 1.5 Years ]
  2. Tolerability [ Time Frame: 1 Year ]
  3. Pharmacokinetic [ Time Frame: 1.5 Years ]
    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.

  4. Antiangiogenic effects [ Time Frame: 1 Year ]

    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.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No


  • Histologically confirmed malignant glioma

    • Grade 3 or 4 disease
    • In first, second, or third recurrence or relapse
  • Multifocal disease allowed


  • 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


  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00387933

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United States, North Carolina
Duke Comprehensive Cancer Center
Durham, North Carolina, United States, 27710
Sponsors and Collaborators
Duke University
National Cancer Institute (NCI)
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Study Chair: David A. Reardon, MD Duke Cancer Institute
Publications of Results:
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Responsible Party: Duke University Identifier: NCT00387933    
Other Study ID Numbers: Pro00006014
First Posted: October 13, 2006    Key Record Dates
Last Update Posted: October 14, 2015
Last Verified: November 2012
Keywords provided by Duke University:
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
Additional relevant MeSH terms:
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Nervous System Neoplasms
Central Nervous System Neoplasms
Neoplasms by Site
Nervous System Diseases
Imatinib Mesylate
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antisickling Agents
Nucleic Acid Synthesis Inhibitors