RATIONALE: AEE788 may stop the growth of tumor cells by blocking the enzymes necessary for their growth and by stopping blood flow to the tumor.

PURPOSE: Phase I/II trial to study the effectiveness of AEE788 in treating patients who have recurrent or relapsed glioblastoma multiforme.

Condition	Treatment or Intervention	Phase
adult glioblastoma recurrent adult brain tumor adult giant cell glioblastoma adult gliosarcoma	Drug: AEE788  Procedure: anti-cytokine therapy  Procedure: antiangiogenesis therapy  Procedure: biological response modifier therapy  Procedure: conventional surgery  Procedure: enzyme inhibitor therapy  Procedure: growth factor antagonist therapy  Procedure: protein tyrosine kinase inhibitor therapy  Procedure: surgery	Phase I Phase II

OBJECTIVES: Primary

• Determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of AEE788 in patients with recurrent or relapsed glioblastoma multiforme who are receiving either non-enzyme-inducing anticonvulsant drugs (non-EIACDs) or no anticonvulsant drugs (ACDs) (phase I).
• Determine the MTD and DLT of this drug in patients who are receiving enzyme-inducing anticonvulsant drugs (EIACDs) (phase I).

Secondary

• Determine the safety and tolerability, including acute and chronic toxic effects, of this drug in these patients.
• Determine the pharmacokinetics of this drug in these patients.
• Compare plasma markers of angiogenesis, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in these patients before and after treatment with this drug.
• Determine the tumor pharmacokinetic levels of this drug at the MTD in patients undergoing tumor biopsy or surgical resection who are receiving non-EIACDs or no ACDs.
• Correlate, using available blood and tumor samples, biological factors with efficacy and response in patients treated with this drug.
• Determine, preliminarily, the efficacy of this drug, in terms of the response rate and progression-free survival at 6 months, in patients who are undergoing tumor biopsy or surgical resection and those not undergoing surgery.

OUTLINE: This is a multicenter, open-label, phase I, dose-escalation study followed by a phase II study. Patients are stratified according to use of enzyme-inducing anticonvulsant drugs (EIACDs) (yes vs no).

• Patients receive oral AEE788 once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients (initial cohort begins with 1 patient) receive escalating doses of AEE788 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 receive treatment at the MTD.
• Patients eligible for tumor biopsy or surgical resection to confirm recurrence or for tumor debulking are assigned to group I. Patients with measurable disease and not eligible for surgery are assigned to group II.
• Group I: Patients who are receiving non-EIACDs or no anticonvulsant drugs receive oral AEE788* once daily for 5 days and then undergo surgery. Patients receiving EIACDs undergo surgery on day 1. All patients receive oral AEE788* once daily on days 15-21. For the second and subsequent courses, patients receive oral AEE788 once daily on days 1-28.
• Group II: Patients receive oral AEE788* once daily on days 1-28. NOTE: *At the MTD determined in phase I

In both groups, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Patients are followed at 7 days and then every 3 months thereafter.

PROJECTED ACCRUAL: A total of approximately 139 patients (3-46 for phase I and 53-93 for phase II [ 33-53 for group I and 20-40 for group II]) will be accrued for this study.

Ages Eligible for Study:  18 Years and above,  Genders Eligible for Study:  Both

Criteria

DISEASE CHARACTERISTICS:

• Histologically confirmed glioblastoma multiforme
• Phase I :
• First or second recurrence or relapse
• At least 1 measurable or evaluable lesion on baseline gadolinium-enhanced (Gd) MRI within the past 3 weeks*
• Phase II:
• First recurrence or relapse
• Group I:
• Baseline Gd MRI within the past 3 weeks*
• Requires tumor biopsy or surgical resection for confirmation of recurrence or for tumor debulking
• Group II:
• At least 1 bidimensionally measurable enhancing mass lesion (1.5 cm^2 area) on baseline Gd MRI within the past 3 weeks* NOTE: *No increase in steroid dose within 7 days prior to Gd MRI
• Multifocal disease allowed

PATIENT CHARACTERISTICS: Age

• 18 and over

Performance status

• Karnofsky 70-100%

Life expectancy

• At least 12 weeks

Hematopoietic

• Absolute neutrophil count ≥ 1,500/mm^3
• Hemoglobin ≥ 9 g/dL
• Platelet count ≥ 100,000/mm^3

Hepatic

• AST and ALT ≤ 2.5 times upper limit of normal (ULN)
• Bilirubin ≤ 1.5 times ULN

Renal

• Creatinine ≤ 1.5 times ULN OR
• Creatinine clearance ≥ 50 mL/min
• Proteinuria negative by dipstick OR
• Total urinary protein ≤ 500 mg AND creatinine clearance ≥ 50 mL/min
• Calcium (corrected) normal or correctable with supplements

Cardiovascular

• LVEF ≥ 45% by MUGA or echocardiogram
• QTc ≤ 480 msec on screening echocardiogram
• No myocardial infarction within the past 6 months
• No complete left bundle branch block
• No obligate use of a cardiac pacemaker
• No synapse time depression > 1 mm in ≥ 2 leads AND/OR T wave inversions in ≥ 2 contiguous leads
• No congenital long QT syndrome
• No history of ventricular or atrial tachyarrhythmias
• No clinically significant resting bradycardia (< 50 beats/min)
• No uncontrolled high blood pressure
• No history of labile hypertension
• No history of poor compliance with an antihypertensive regimen
• No unstable angina pectoris
• No symptomatic congestive heart failure

Other

• Potassium normal or correctable with supplements
• Magnesium normal or correctable with supplements
• Phosphorus normal or correctable with supplements
• No other malignancy that is clinically significant or requires active intervention
• No uncontrolled diabetes
• No active or uncontrolled infection
• No unresolved diarrhea > grade 1
• No peripheral neuropathy > grade 1
• No gastrointestinal function impairment or disease that may alter absorption of study drug (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)
• No claustrophobia, obesity, or ferromagnetic metal implant that would preclude MRI scanning
• No concurrent severe and/or uncontrolled medical condition that would preclude study participation
• HIV negative
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective barrier contraception

PRIOR CONCURRENT THERAPY: Biologic therapy

• More than 2 weeks since prior hematopoietic colony-stimulating factor (e.g., filgrastim [G-CSF] or sargramostim [GM-CSF]) therapy
• More than 2 weeks since prior immunotherapy and recovered
• No prior epidermal growth factor receptor- or HER2/neu-directed therapies*
• No prior vascular endothelial growth factor (VEGF) or VEGF receptor-directed therapies*
• No other concurrent biologic therapy NOTE: * Phase II only

Chemotherapy

• More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin) and recovered
• No concurrent chemotherapy

Endocrine therapy

• See Disease Characteristics
• Concurrent steroids allowed provided dose has not increased within the past 7 days

Radiotherapy

• More than 4 weeks since prior radiotherapy and recovered
• No concurrent radiotherapy

Surgery

• See Disease Characteristics
• Phase I:
• More than 2 weeks since prior biopsy or surgical resection
• Phase II:
• More than 8 weeks since prior biopsy or surgical resection
• More than 2 weeks since prior major non-CNS surgery and recovered

Other

• More than 4 weeks since prior investigational drugs and recovered
• No concurrent digoxin
• No concurrent verapamil
• No concurrent therapeutic-dose warfarin
• No concurrent medications that may prolong the QT interval, including:
• Class IA antiarrhythmics (e.g., quinidine, procainamide, disopyramide)
• Class III antiarrhythmics (e.g., amiodarone, sotalol, bretylium, ibutilide)
• Phenothalazine antipsychotics (e.g., thioridazine, mesoridazine, chlorpromazine)
• Tricyclic antidepressants (e.g., amitriptyline, imipramine, desipramine, doxepin)
• Macrolide antibiotics (e.g., erythromycin, clarithromycin)
• Azole antifungals (e.g., ketoconazole)
• Antimalarials (e.g., halofantrine, quinine, chloroquine, mefloquine)
• Moxifloxacin
• Gatifloxacin
• Pimozide
• Risperidone or ziprasidone
• Venlafaxine
• Maprotiline
• Lithium
• Pentamidine
• Droperidol
• Dolasetron
• Tamoxifen
• Tacrolimus
• No other concurrent investigational agents

California
      Jonsson Comprehensive Cancer Center, UCLA, Los Angeles,  California,  90095,  United States; Recruiting

Study chairs or principal investigators

Timothy F. Cloughesy, MD,  Principal Investigator,  Jonsson Comprehensive Cancer Center   

Study ID Numbers:  CDR0000367487; UCLA-0312056-01; NOVARTIS-CAEE788A2103
Record last reviewed:  May 2004
Record first received:  June 10, 2004
ClinicalTrials.gov Identifier:  NCT00085215
Health Authority: Unspecified
ClinicalTrials.gov processed this record on 2004-11-08