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

This study has been completed.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Duke University
ClinicalTrials.gov Identifier:
NCT00387933
First received: October 12, 2006
Last updated: June 3, 2013
Last verified: November 2012
  Purpose

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 Intervention Phase
Brain and Central Nervous System Tumors
Drug: hydroxyurea
Drug: imatinib mesylate
Drug: vatalanib
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I Dose Escalation of Gleevec in Combination With PTK787/ZK 222584 (PTK/ZK) Plus Hydroxyurea

Resource links provided by NLM:


Further study details as provided by Duke University:

Primary Outcome Measures:
  • Maximum tolerated dose and dose-limiting toxicity of imatinib mesylate and vatalanib when administered with hydroxyurea [ Time Frame: 1 Year ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Safety [ Time Frame: 1.5 Years ] [ Designated as safety issue: Yes ]
  • Tolerability [ Time Frame: 1 Year ] [ Designated as safety issue: Yes ]
  • Pharmacokinetic [ Time Frame: 1.5 Years ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]

    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.



Enrollment: 37
Study Start Date: July 2005
Primary Completion Date: January 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00387933

Locations
United States, North Carolina
Duke Comprehensive Cancer Center
Durham, North Carolina, United States, 27710
Sponsors and Collaborators
Duke University
Investigators
Study Chair: David A. Reardon, MD Duke Cancer Institute
  More Information

Additional Information:
Publications:
Responsible Party: Duke University
ClinicalTrials.gov Identifier: NCT00387933     History of Changes
Other Study ID Numbers: Pro00006014, DUMC-7019-06-3R1, NOVARTIS-DUMC-7019-06-3R1
Study First Received: October 12, 2006
Last Updated: June 3, 2013
Health Authority: United States: Federal Government
United States: Food and Drug Administration
United States: Institutional Review Board

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:
Nervous System Neoplasms
Central Nervous System Neoplasms
Glioma
Neoplasms by Site
Neoplasms
Nervous System Diseases
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Imatinib
Hydroxyurea
Vatalanib
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Antisickling Agents
Hematologic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Nucleic Acid Synthesis Inhibitors
Protein Kinase Inhibitors

ClinicalTrials.gov processed this record on July 24, 2014