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

Sponsor

Duke University (Other)

Overall Status

Completed

CT.gov ID

NCT00387933

Collaborator

National Cancer Institute (NCI) (NIH)

Enrollment

Location

Arm

Study Details

Study Description

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

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 Design

Study Type:

Interventional

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 :

Jul 1, 2005

Actual Primary Completion Date :

Jan 1, 2009

Arms and Interventions

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 Names: Gleevec Drug: vatalanib Other Names: PTK787

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:

hydrea

Drug: imatinib mesylate

Other Names:

Gleevec

Drug: vatalanib

Other Names:

PTK787

Outcome Measures

Primary Outcome Measures

Maximum tolerated dose and dose-limiting toxicity of imatinib mesylate and vatalanib when administered with hydroxyurea [1 Year]

Secondary Outcome Measures

Safety [1.5 Years]
Tolerability [1 Year]
Pharmacokinetic [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 [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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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