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Phase I Dose Escalation of Gleevec in Combination With PTK787/ZK 222584 (PTK/ZK) Plus Hydroxyurea

Phase 1
18 Years
Not Enrolling
Brain and Central Nervous System Tumors

Thank you

Trial Information

Phase I Dose Escalation of Gleevec in Combination With PTK787/ZK 222584 (PTK/ZK) Plus Hydroxyurea


- 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.

Inclusion Criteria


- 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

- 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

- Prior epoetin alfa allowed

- No concurrent warfarin

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum tolerated dose and dose-limiting toxicity of imatinib mesylate and vatalanib when administered with hydroxyurea

Outcome Time Frame:

1 Year

Safety Issue:


Principal Investigator

David A. Reardon, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Duke Cancer Institute


United States: Federal Government

Study ID:




Start Date:

July 2005

Completion Date:

Related Keywords:

  • Brain and Central Nervous System Tumors
  • 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
  • Nervous System Neoplasms
  • Central Nervous System Neoplasms
  • Glioma



Duke Comprehensive Cancer CenterDurham, North Carolina  27710