ph i gleevec in combo w rad001 + hydroxyurea for pts w recurrent mg

Conditions: Glioblastoma; Gliosarcoma

Summary: primary objective to determine maximum tolerated dose \& dose limiting toxicity of imatinib mesylate \& rad001 when combined w fixed doses of hydroxyurea among pts w recurrent gbm who are on \& not on enzyme-inducing anti-convulsants including pts not on anti-epileptic drugs secondary objective to assess safety \& tolerability of imatinib mesylate in combo w rad001 \& hydroxyurea in this population to characterize single-dose \& repeated-dose pharmacokinetic profiles of imatinib mesylate \& rad001 combo therapy in this pt population. to assess antiangiogenic effects, pre- and post-treatment, of imatinib mesylate, rad001 \& hydroxyurea combo therapy, using dce-mri to evaluate changes in extent of vascular permeability, perfusion \& relative tumor blood volume; to explore assessment of tumor cellularity \& tumor cell death by changes in dwi-mri as quantitated by apparent diffusion coefficient maps.

this is open-label, single center, 1-arm ph i dose-escalation study of continuous, daily doses of imatinib mesylate \& rad001 administered orally in combination w fixed doses of hydroxyurea in adult pts w recurrent or relapsing glioblastoma multiforme. study format includes classical "3+3" dose escalation design to determine mtd \& dlt of imatinib mesylate + rad001 when combined w hydroxyurea among gbm pts. pts will be stratified based on whether they who are receiving eiacd \& each stratum will independently dose escalate. additionally, study will characterize safety, tolerability, biologic activity, \& pharmacokinetic profile of this combo therapy.

Eligibility criteria:
inclusion criteria: * pts w confirmed gbm, gs, aa, ao \& aoa are presenting in 1st, 2nd/3rd recurrence/relapse * pts without tumor biopsy \<1 wk/surgical resection \<2 wks prior to starting study drug * for stratum of non-eiaed pts, each pts off all enzyme inducing anticonvulsants for \>2 wks prior to starting study drug * pts should be on non-increasing dose of steroids for \>7 days prior to obtaining baseline gd-mri of brain * pts should be on non-increasing dose of steroids for \>7 days prior to starting study drug * pts w previous implantation of gliadel may be eligible after discussion between investigator \& sponsor * multifocal disease is eligible * age \>18 yrs * kps \>70 * hematology: anc\>1.5 x 10\^9/l, hgb\>9 g/dl, platelets\>100 x 10\^9/l * biochemistry: k≥ lln/correctable w supplement, total ca≥ lln/correctable w supplement, mg≥ lln/correctable w supplement, p≥ lln/correctable w supplement, ast/sgot \& alt/sgpt \<2.5 x uln, serum bilirubin \<1.5 x uln, serum creatinine \<1.5 x uln/measured 24hr crcl\<0 ml/min/1.73m2, \& cholesterol≤ 00 mg/dl \& triglyceride≤2.5 uln * life expectancy ≥12wks * written informed consent obtained prior to any screening procedures exclusion criteria: * pts w any peripheral neuropathy ≥ctcae gr2 * pts w unresolved diarrhea ≥ctcae gr2 * history of impaired cardiac function * obligate use of cardiac pacemaker, congenital long qt syndrome, history or presence of ventricular or atrial tachyarrhythmias, clinically significant resting bradycardia , right bundle branch block + left anterior hemiblock * other clinically significant cardiac diseases * uncontrolled db * active or uncontrolled infection requiring intravenous antibiotics * impairment of gi function/gi disease that may significantly alter absorption of gleevec, hydroxyurea and/or rad001 * acute/chronic liver/renal disease * other concurrent severe and/or uncontrolled medical condition that could cause unacceptable safety risks/compromise compliance w protocol * treatment w any hematopoietic colony-stimulating factor ≤2wks prior to starting study drug. erythropoietin is allowed * pts w history of chf/arrhythmias who are receiving treatment w digoxin/verapamil, \& treatment cannot be discontinued/switched to different drug prior to starting study drug * pts taking warfarin sodium * pts received treatment w pdgf/mtor directed therapies * pts received chemo ≤ 4wks prior to starting study drug/have not recovered from side effects of such therapy * pts received immunotherapy ≤2 wks prior to starting study drug/have not recovered from side effects of such therapy * pts received investigational drugs ≤4 wks prior to starting study drug/have not recovered from side effects of such therapy * pts received xrt ≤4 wks prior to starting study drug/have not recovered from side effects of such therapy * pts undergone major non-cns surgery ≤2 wks prior to starting study drug/pts have not recovered from side effects of such therapy * cardiac pacemaker, ferromagnetic metal implants other than those approved as safe for use in mr scanners, claustrophobia, obesity * female pts are pregnant/breast feeding,/adults of reproductive potential not employing effective method of birth control. barrier contraceptives must be used throughout trial in both sexes. oral, implantable/injectable contraceptives may be affected by cytochrome p450 interactions, \& are therefore not considered effective for study. women of childbearing potential have negative serum pregnancy test 48hrs prior to administration of gleevec, hydroxyurea and/or rad001. * known diagnosis of hiv infection * pts w history of another primary malignancy that is currently clinically significant/currently requires active intervention * pts unwilling to/unable to comply w protocol

Keywords: glioblastoma gliosarcoma gbm brain tumor rad0001 hydroxyurea gleevec imatinib droxia everolimus hydrea hydroxycarbamide recurrent gbm imatinib mesylate glioblastoma multiforme