Primary Objective To determine maximum tolerated dose & dose limiting toxicity of vandetanib
when combo w standard dosing of etoposide among pts w recurrent malignant glioma who are on
& not on enzyme-inducing anti-epileptic drugs Secondary Objectives To assess safety &
tolerability of vandetanib + etoposide in population To evaluate pharmacokinetics of
vandetanib among malignant glioma pts on & not on EIAEDs when combo w etoposide Exploratory
Objective To evaluate for evidence of anti-tumor activity of study regimen among recurrent
malignant glioma pts including radiographic response rate, 6-month progression free survival
rate & median PFS
Sample size will be based on modified, classical "3+3" dose escalation design. Primary
safety & efficacy analysis will be conducted on all subject data at time all subjects who
are still receiving study drug will have completed at least 4 cycles of treatment. Most
common AEs associated w vandetanib are rash, diarrhea, & asymptomatic QTc prolongation.
Protracted oral dosing of etoposide is associated w toxicity that is mild in most pts &
consists mainly of myelosuppression & diarrhea. Less commonly, protracted etoposide dosing
has been associated w more significant hematologic toxicity.
Inclusion Criteria:
Pts have baseline evaluations ≤14days prior to 1st dose of study drug unless otherwise
specified
- Pts w confirmed MG who are recurrence/relapse
- Pts may not have stereotactic tumor biopsy < 1wk or surgical resection or open biopsy
< 4wks before starting study drug
- For stratum of non-EIAED pts, each pt must be off all EIAEDs for >2wks prior to
starting study drug; similarly for stratum of EIAED pts, each pt must 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
- KPS ≥70
- Absolute Neutrophil Count ≥1. 0 x 10 9/L
- Hgb ≥9 g/dL
- Platelets ≥100 x 10 9/L
- Serum creatinine ≤1. 5 x ULRR or measured 24-hr CrCl ≥50mL/min/1. 73m2
- Life expectancy ≥12wks
- Written informed consent obtained prior to screening procedures
- Negative Beta-HCG pregnancy test for women of child-bearing potential
Exclusion Criteria:
- Labortoary Results:
- Serum direct bilirubin >1. 5 x ULN of reference range
- Serum creatinine >1. 5 x ULRR & CrCl <30 mL/min
- Potassium, <4. 0 mmol/L despite supplementation; serum calcium, Mg out of normal range
despite supplementation
- ALT or 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/which
would jeopardize compliance w protocol
- Clinically significant cardiovascular event such as myocardial infarction, superior
vena cava syndrome, New York Heart Association classification of heart disease >2
within 3 months before entry; or presence of cardiac disease that, in opinion of
Investigator, increases risk of ventricular arrhythmia
- History of arrhythmia which is symptomatic/requires treatment/asymptomatic sustained
ventricular tachycardia. Atrial fibrillation, controlled on medication is not
excluded
- Previous history of QTc prolongation as result from other medication that required
discontinuation of that medication
- Congenital long QT syndrome, or 1st degree relative w unexplained sudden death <40yrs
- Presence of left bundle branch block
- QTc with Bazett's correction that's unmeasureable, or ≥ 480msec on screening EEG.
- Any concomitant medication that may cause QTc prolongation, induce Torsades de
Pointes/induce 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
- Women who are currently pregnant/breast feeding
- Previous/current malignancies of other histologies the last year, w exception of
cervical carcinoma in situ & adequately treated basal cell/ squamous cell carcinoma
of skin
- Receipt of any investigational agents <30 days prior to commencing study treatment
unless pt has recovered from all anticipated toxicities of investigational agent
- Last dose of prior chemo discontinued <4wks before start of study therapy unless pt
has recovered from all anticipated toxicities of chemo
- Last XRT <4wks before start of study therapy, unless pt has recovered from all
anticipated toxicities of XRT
- Any unresolved toxicity >CTC gr1 from previous anti-cancer therapy
- Previous enrollment/randomization of treatment in present study
- Major surgery <4wks/incompletely healed surgical incision before starting study
therapy
- Patients who have received prior oral VEGFR, EGFR or PDGFR-directed therapies.
Patients who received prior Avastin will be eligible as long as at least 6 wks has
elapsed since last dose.
- Pts taking warfarin sodium
James J Vredenburgh, MD, Phone: (919) 681-3824, Email: james.vredenburgh@duke.edu
