AEE788 and Everolimus in Treating Patients With Recurrent or Relapsed Glioblastoma Multiforme

Study Overview
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Brief Summary
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RATIONALE: AEE788 and everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Giving AEE788 together with everolimus may kill more tumor cells. PURPOSE: This phase I/II trial is studying the side effects and best dose of AEE788 when given together with everolimus and to see how well they work in treating patients with recurrent or relapsed glioblastoma multiforme.

Detailed Description
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OBJECTIVES: Primary Determine the maximum tolerated dose and dose-limiting toxicity of AEE788 when administered in combination with 1 of 2 different doses of everolimus in patients with recurrent or relapsed glioblastoma multiforme. Secondary Determine the safety and tolerability of this regimen, including acute and chronic toxic effects, in these patients. Determine the single-dose and repeated-dose pharmacokinetic profile of this regimen in these patients. Determine, preliminarily, the efficacy of this regimen, in terms of response rate, progression-free survival, and overall survival, in these patients. (Phase II) Determine the antiangiogenic effects of this regimen in these patients. OUTLINE: This is an open-label, multicenter, dose-escalation study of AEE788. Phase I: Patients are assigned to 1 of 2 treatment groups. Group 1: Patients receive oral AEE788 once daily and oral everolimus once daily on days 1-28. Group 2: Beginning at the first occurrence of dose-limiting toxicity in group 1, patients receive AEE788 as in group 1 and a higher-dose of oral everolimus once daily on days 1-28. In both groups, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients per group receive escalating doses of AEE788 until the maximum tolerated dose is determined. Phase II: Patients are assigned to 1 of 2 treatment groups according to eligibility for surgery. Group 1 (eligible for tumor biopsy, surgical resection, or tumor debulking): Patients receive oral AEE788 once daily at the MTD and oral everolimus once daily for 5-9 days. Patients then undergo surgery. Beginning 15-21 days after surgery, patients receive oral AEE788 and oral everolimus once daily on days 1-28. Group 2 (ineligible for surgery): Patients receive oral AEE788 once daily at the MTD and oral everolimus once daily on days 1-28. In both groups, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. In both phases, if treatment with AEE788 or everolimus is stopped due to toxicity, patients may continue to receive AEE788 or everolimus alone once daily. After the completion of study treatment, patients are followed every 3 months for as long as the investigator deems necessary.

Official Title
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A Phase IB/II Multicenter, Two-Arm, Dose-Escalation Study of Oral AEE788 Administered in Combination With Oral RAD001 on a Continuous Once Daily Dosing Schedule in Adult Patients With First or Second Recurrent or Relapsing Glioblastoma Multiforme

Conditions
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Brain and Central Nervous System Tumors

Intervention / Treatment
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* Drug: AEE788
* Drug: everolimus


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed glioblastoma multiforme, meeting 1 of the following criteria: Phase I In first or second recurrence or relapse At least 1 measurable or evaluable enhancing lesion by gadolinium MRI (Gd-MRI) of the brain within the past 3 weeks Phase II, group 1 In first or second recurrence or relapse by Gd-MRI of the brain within the past 3 weeks Requires tumor biopsy OR surgical resection for tumor debulking or for confirmation of recurrence Phase II, group 2 In first recurrence or relapse At least 1 bidimensionally measurable enhancing lesion (≥ 1.5 cm^2 using product of the largest perpendicular diameters) by Gd-MRI of the brain within the past 3 weeks Multifocal disease allowed PATIENT CHARACTERISTICS: 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 Bilirubin ≤ 1.5 times upper limit of normal (ULN) AST and ALT ≤ 2.5 times ULN No acute or chronic liver disease Renal Total calcium (corrected) normal* Creatinine ≤ 1.5 times ULN OR Creatinine clearance ≥ 50 mL/min No proteinuria by dipstick OR Total urinary protein ≤ 500 mg AND creatinine clearance ≥ 50 mL/min by 24-hour urine collection No acute or chronic renal disease NOTE: *Supplements allowed Cardiovascular LVEF ≥ 45% by MUGA or echocardiogram No complete left bundle branch block No requirement for a cardiac pacemaker No congenital long QT syndrome No ventricular or atrial tachyarrhythmias No clinically significant resting bradycardia, defined as < 50 beats per minute QTc ≤ 480 msec by ECG No right bundle branch block and left anterior hemiblock (bifascicular block) No uncontrolled hypertension OR history of labile hypertension No unstable angina pectoris OR angina pectoris occurrence within the past 3 months No congestive heart failure No acute myocardial infarction within the past 3 months No history of poor compliance with an antihypertensive regimen No other impaired cardiac function or clinically significant cardiac disease Gastrointestinal No unresolved diarrhea ≥ grade 2 No impairment of gastrointestinal (GI) function or GI disease that would significantly alter absorption of study drugs, including any of the following: Ulcerative disease Uncontrolled nausea Vomiting Malabsorption syndrome Other Not pregnant or nursing Negative pregnancy test Fertile patients must use effective barrier contraception Potassium normal* Magnesium normal* Phosphorus normal* Cholesterol ≤ 300 mg/dL (treatment allowed) Triglycerides ≤ 2.5 times ULN (treatment allowed) No known HIV positivity No peripheral neuropathy ≥ grade 2 No uncontrolled diabetes No active or uncontrolled infection No other severe and/or uncontrolled medical condition that would preclude study participation or compliance No contraindication to MRI, including any of the following: Cardiac pacemaker Ferromagnetic metal implants other than those approved as safe for use with magnetic resonance scanners (e.g., some types of aneurysm clips or shrapnel) Claustrophobia Obesity exceeding magnetic resonance equipment limits No other clinically significant primary malignancy requiring active intervention NOTE: *Supplements allowed PRIOR CONCURRENT THERAPY: Biologic therapy More than 2 weeks since prior hematopoietic colony-stimulating factors (e.g., filgrastim [G-CSF] or sargramostim [GM-CSF]) except epoetin alfa More than 2 weeks since prior immunotherapy and recovered No concurrent biologic therapy No concurrent prophylactic hematopoietic growth factors (e.g., G-CSF or GM-CSF) unless approved by the study sponsor Chemotherapy More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin) and recovered Prior polifeprosan 20 with carmustine implant (Gliadel® wafer) allowed No other concurrent chemotherapy Endocrine therapy Must be on stable or deceasing doses of steroids for at least 7 days before baseline Gd-MRI of the brain and before starting study drug No concurrent tamoxifen Radiotherapy More than 4 weeks since prior radiotherapy and recovered No concurrent radiotherapy Surgery More than 1 week since prior tumor biopsy More than 2 weeks since prior surgical resection More than 2 weeks since prior major non-CNS surgery and recovered No prior small bowel resection Other At least 2 weeks since prior and no concurrent enzyme-inducing anticonvulsant drugs More than 4 weeks since prior investigational drugs and recovered No prior epidermal growth factor receptor- or ErbB-2-directed therapy (phase II only) No prior vascular endothelial growth factor (VEGF) or VEGF receptor-directed therapy (phase II only) No prior mTOR-directed therapy (phase II only) No concurrent therapeutic warfarin No concurrent treatment with any medication that may prolong QT interval, including any of the following: Quinidine Procainamide Disopyramide Amiodarone Sotalol Bretylium Ibutilide Thioridazine Mesoridazine Chlorpromazine Amitriptyline Imipramine Desipramine Doxepin Erythromycin Clarithromycin Ketoconazole Halofantrine Quinine Chloroquine Mefloquine Moxifloxacin Gatifloxacin Pimozide Risperidone Ziprasidone Venlafaxine Maprotiline Lithium Pentamidine Droperidol Dolasetron No concurrent digoxin or verapamil No concurrent tacrolimus No other concurrent investigational agents

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AEE788 200 mg + RAD001 5 mg<br>AEE788 200 mg qd, RAD001 5 mg qd | Drug: AEE788<br>* AEE788 was available in the form of a hard gelatin capsule of 50 mg or 100 mg strengths and packaged in bottles.<br>Drug: everolimus<br>* Everolimus was formulated as tablets of 2.5 mg and 5 mg strength and supplied in blister packs.<br>* Other names: RAD001;|
| Experimental: AEE788 150 mg + RAD001 5mg<br>AEE788 150 mg qd, RAD001 5 mg qod | Drug: AEE788<br>* AEE788 was available in the form of a hard gelatin capsule of 50 mg or 100 mg strengths and packaged in bottles.<br>Drug: everolimus<br>* Everolimus was formulated as tablets of 2.5 mg and 5 mg strength and supplied in blister packs.<br>* Other names: RAD001;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose and dose-limiting toxicity of AEE788 |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety |  |  | 
| Tolerability |  |  | 
| Single-dose and repeated-dose pharmacokinetic profile |  |  | 
| Efficacy (response rate, progression-free survival, and overall survival) |  |  | 
| Antiangiogenic effects |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adult glioblastoma, recurrent adult brain tumor, adult giant cell glioblastoma, adult gliosarcoma