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

Brain and Central Nervous System Tumors Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00387933
• Other study ID #: Pro00006014
• Secondary ID: DUMC-7019-06-3R1
• Status: Completed
• Phase: Phase 1
• First received: October 12, 2006
• Last updated: October 11, 2015
• Start date: July 2005

Study information

• Verified date: November 2012
• Source: Duke University
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal GovernmentUnited States: Food and Drug AdministrationUnited States: Institutional Review Board
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 37
• Est. primary completion date: January 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

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

Related Conditions & MeSH terms

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

Intervention

Drug:
• hydroxyurea

• imatinib mesylate

• vatalanib

Locations

Country	Name	City	State
United States	Duke Comprehensive Cancer Center	Durham	North Carolina

Sponsors (2)

Lead Sponsor	Collaborator
Duke University	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

References & Publications (1)

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 (PTK7 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maximum tolerated dose and dose-limiting toxicity of imatinib mesylate and vatalanib when administered with hydroxyurea		1 Year	Yes
Secondary	Safety		1.5 Years	Yes
Secondary	Tolerability		1 Year	Yes
Secondary	Pharmacokinetic	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.	1.5 Years	No
Secondary	Antiangiogenic effects	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.	1 Year	No