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

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ClinicalTrials.gov Identifier: NCT00387933
Recruitment Status : Completed
First Posted : October 13, 2006
Last Update Posted : October 14, 2015
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Duke University

Tracking Information
First Submitted Date  ICMJE October 12, 2006
First Posted Date  ICMJE October 13, 2006
Last Update Posted Date October 14, 2015
Study Start Date  ICMJE July 2005
Actual Primary Completion Date January 2009   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 30, 2012)
Maximum tolerated dose and dose-limiting toxicity of imatinib mesylate and vatalanib when administered with hydroxyurea [ Time Frame: 1 Year ]
Original Primary Outcome Measures  ICMJE Not Provided
Change History Complete list of historical versions of study NCT00387933 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: November 30, 2012)
  • Safety [ Time Frame: 1.5 Years ]
  • Tolerability [ Time Frame: 1 Year ]
  • 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.
  • 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.
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Outcome Measures  ICMJE Not Provided
Original Other Outcome Measures  ICMJE Not Provided
 
Descriptive Information
Brief Title  ICMJE Imatinib Mesylate, Vatalanib, and Hydroxyurea in Treating Patients With Recurrent or Relapsed Malignant Glioma
Official Title  ICMJE Phase I Dose Escalation of Gleevec in Combination With PTK787/ZK 222584 (PTK/ZK) Plus Hydroxyurea
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.

Detailed Description

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.

Study Type  ICMJE Interventional
Study Phase Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Brain and Central Nervous System Tumors
Intervention  ICMJE
  • Drug: hydroxyurea
    Other Names:
    • HU
    • hydrea
  • Drug: imatinib mesylate
    Other Name: Gleevec
  • Drug: vatalanib
    Other Name: PTK787
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
Publications * Reardon DA, Egorin MJ, Desjardins A, Vredenburgh JJ, Beumer JH, Lagattuta TF, Gururangan S, Herndon JE 2nd, Salvado AJ, Friedman HS. Phase I pharmacokinetic study of the vascular endothelial growth factor receptor tyrosine kinase inhibitor vatalanib (PTK787) plus imatinib and hydroxyurea for malignant glioma. Cancer. 2009 May 15;115(10):2188-98. doi: 10.1002/cncr.24213.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: November 30, 2012)
37
Original Enrollment  ICMJE Not Provided
Study Completion Date Not Provided
Actual Primary Completion Date January 2009   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender
Sexes Eligible for Study: All
Ages 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00387933
Other Study ID Numbers  ICMJE Pro00006014
DUMC-7019-06-3R1
NOVARTIS-DUMC-7019-06-3R1
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement Not Provided
Responsible Party Duke University
Study Sponsor  ICMJE Duke University
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Study Chair: David A. Reardon, MD Duke Cancer Institute
PRS Account Duke University
Verification Date November 2012

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP