Ph I Zactima + Imatinib Mesylate & Hydroxyurea for Pts w Recurrent Malignant Glioma

• Status: Completed
• Trial end date: 2009-04-01
• Target enrollment: 0
• Participant gender: All

Summary

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

• Phase: Phase 1
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Annick Desjardins
• Collaborators: AstraZeneca; Novartis Pharmaceuticals
• Treatments: Hydroxyurea; Imatinib Mesylate

Criteria

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