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

NCT ID: NCT00387933

Last Updated: 2015-10-14

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 37 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2005-07-31

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.

Conditions

Brain and Central Nervous System Tumors

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

hydroxyurea

Intervention Type: DRUG

imatinib mesylate

Intervention Type: DRUG

vatalanib

Intervention Type: DRUG

Interventions

hydroxyurea

Intervention Type: DRUG

imatinib mesylate

Intervention Type: DRUG

vatalanib

Intervention Type: DRUG

Other Intervention Names

HU; hydrea; Gleevec; PTK787

Eligibility Criteria

Inclusion 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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

Duke University

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

David A. Reardon, MD

Role: STUDY_CHAIR

Duke Cancer Institute

Locations

Duke Comprehensive Cancer Center

Durham, North Carolina, United States

Countries

United States

References

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.

Reference Type: RESULT

PMID: 19248046 (View on PubMed)

Other Identifiers

DUMC-7019-06-3R1

Identifier Type: -

Identifier Source: secondary_id

NOVARTIS-DUMC-7019-06-3R1

Identifier Type: -

Identifier Source: secondary_id

Pro00006014

Identifier Type: -

Identifier Source: org_study_id