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.
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
