Primary Objective To determine maximum tolerated dose & dose limiting toxicity of Zactima
when combined w standard dosing of imatinib mesylate & hydroxyurea among pts w recurrent
malignant glioma who are on & not on enzyme-inducing anti-epileptic drugs Secondary
Objectives To assess safety & tolerability of Zactima + imatinib mesylate & hydroxyurea To
evaluate pharmacokinetics of Zactima among MG pts on & not on enzyme inducing anti-epileptic
drugs (EIAEDs) when combo w imatinib mesylate & hydroxyurea To evaluate pharmacokinetics of
imatinib mesylate among MG pts on & not on EIAEDs when combo w Zactima & hydroxyurea
Exploratory Objective To evaluate for evidence of anti-tumor activity of study regimen among
recurrent malignant glioma (RMG) pts including radiographic response rate, 6-month
progression free survival (PFS) rate & median PFS
Inclusion Criteria:
- Pts have baseline evaluations performed ≤14days prior to 1st dose of study drug
unless otherwise specified. Written informed consent must be obtained from pt prior
to enrollment
- Pts w MG who are presenting in 1st, 2nd or 3rd recurrence or relapse
- Pts may not have tumor biopsy <1 wk or surgical resection <2wks
- For stratum of non-EIAED pts, each pt be off all EIAEDs for >2 wks prior to starting
study drug; similarly for stratum of EIAED pts, each pt be on EIAED 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
- Multifocal disease is eligible
- Age >18yrs
- Karnofsky Performance Status (KPS) of >70
- Absolute neutrophil count (ANC) > 1. 0 x 10 9/L
- Hgb>g/dL
- Platelets>100 x 10 9/L
- Serum creatinine<1. 5 x upper limit of normal (ULN)/measured 24hr creatinine clearance
(CrCl) >50 milliliters/min/1. 73m
- Life ≥12wks
- Written informed consent obtained prior to any screening procedures
Exclusion Criteria:
- Serum bilirubin >1. 5x ULN of reference range
- Serum creatinine >1. 5 x Upper Limit of the Reference Range (ULRR)/CrCl <50
milliliters/min
- K<4. 0 mmol/L despite supplementation; serum Ca/Mg out of normal range despite
supplementation
- alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2. 5 x ULRR
- Evidence of severe/uncontrolled systemic disease or any concurrent condition which in
Investigator's opinion makes it undesirable for pt to participate in trial or which
would jeopardize compliance w protocol
- Clinically significant cardiac event such as myocardial infarction; New York Heart
Association (NYHA) classification of heart disease >2 within 3 months before
entry;/presence of cardiac disease that, in opinion of Investigator, increases risk
of ventricular arrhythmia or dysfunction; ejection fraction<50 percent prior to study
initiation
- History of arrhythmia-symptomatic/requires treatment/asymptomatic sustained
ventricular tachycardia. Atrial fibrillation, controlled on medication is not
excluded
- Previous history of corrected QT interval (QTc) prolongation as result from other
medication that required discontinuation of that medication
- Congenital long QT syndrome/1st degree relative with unexplained sudden death under
40 years
- Presence of left bundle branch block
- QTc with Bazett's correction that is unmeasurable/>480 msec on screening ECG. If pt
has QTc >480 msec on screening ECG, screen ECG may be repeated twice. Average QTc
from 3 screening ECGs must be <480 msec in order for pt to be eligible for study
- Any concomitant medication that may cause QTc prolongation, induce Torsades de
Pointes/induce cytochrome P450 3A4 (CYP3A4) function except for EIAEDs
- Hypertension not controlled by medical therapy
- Currently active diarrhea that may affect ability of pt to absorb study
regimen/tolerate diarrhea
- Pregnant/breast feeding
- Previous/current malignancies of other histologies <1yr, w exception of cervical
carcinoma in situ & adequately treated basal cell/squamous cell carcinoma of skin
- Receipt of any investigational agents within 30 days prior to commencing study
treatment unless pt has recovered from all anticipated toxicities of investigational
agent
- Last dose of prior chemo discontinued <4 wks before start of study therapy unless pt
has recovered from all anticipated toxicities of chemo
- Last radiation therapy (XRT) <4wks before start of study therapy, unless pt has
recovered from all anticipated toxicities of XRT
- Any unresolved toxicity > Common Terminology Criteria (CTC) grade 1 from previous
anti-cancer therapy
- Previous enrollment/randomization of treatment in present study
- Major surgery <4 wks/incompletely healed surgical incision before starting study
therapy
- Pts who have received prior oral VEGFR, EGFR/PDGFR-directed therapies
- Pts who are taking warfarin sodium
