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Phase I Dose Escalation of Vandetanib (Zactima, ZD6474) in Combination With Etoposide for Malignant Gliomas

Phase 1
18 Years
Not Enrolling
Gliosarcoma, Glioblastoma

Thank you

Trial Information

Phase I Dose Escalation of Vandetanib (Zactima, ZD6474) in Combination With Etoposide for Malignant Gliomas

This is open-label, single center, 2-cohort phase I dose-escalation study of vandetanib
administered orally on continuous daily dosing schedule + oral etoposide among adult
patients with recurrent or relapsing malignant glioma. Patients will be stratified based on
whether they are receiving EIAEDs & each stratum will independently dose escalate. Dose of
vandetanib will be increased in successive cohorts of patients. Etoposide will be given
daily at a dose of 50mg/day for 21 days followed by 7 days with no etoposide. Cohorts of 3-6
subjects will accrue at each dose level until maximum tolerated dose (MTD) is defined.
Subjects will be adult patients with histologically confirmed malignant glioma who are
presenting at time of recurrence/relapse. Up to 48 subjects will be enrolled.

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 adverse events (AEs) associated with vandetanib are rash, diarrhea, & asymptomatic
QTc prolongation. Protracted oral dosing of etoposide is associated with toxicity that is
mild in most patients & consists mainly of myelosuppression & diarrhea. Less commonly,
protracted etoposide dosing has been associated w more significant hematologic toxicity.

Inclusion Criteria:

Patients have baseline evaluations ≤14days prior to 1st dose of study drug unless
otherwise specified

- Patients with confirmed malignant glioma (MG) who are recurrence/relapse

- Patients may not have stereotactic tumor biopsy < 1 week or surgical resection or
open biopsy < 4 weeks before starting study drug

- For stratum of non-EIAED patients, each patient must be off all EIAEDs for > 2 weeks
prior to starting study drug; similarly for stratum of EIAED patients, each patient
must be on EIAED for >2 weeks prior to starting study drug

- Patients should be on non-increasing dose of steroids for >7 days prior to obtaining
baseline MRI with gadolinium (Gd-MRI) of brain

- Patients should be on non-increasing dose of steroids for >7 days prior to starting
study drug

- Multifocal disease is eligible

- Age ≥ 18 years

- Karnofsky Performance Status (KPS) ≥70

- Absolute Neutrophil Count ≥1.0 x 10 9/L

- Hemoglobin (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 ≥ 12 weeks

- Written informed consent obtained prior to screening procedures

- Negative Beta-HCG pregnancy test for women of child-bearing potential

Exclusion Criteria:

- Laboratory Results:

- Serum direct bilirubin >1.5 x upper limit of normal (ULN) of reference range

- Serum creatinine >1.5 x ULRR & CrCl <30 mL/min

- Potassium, <4.0 mmol/L despite supplementation; serum calcium, magnesium 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 patient to participate in trial or
which would jeopardize compliance with 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

- Previous history of QTc prolongation as result from other medication that required
discontinuation of that medication

- Congenital long QT syndrome, or 1st degree relative with unexplained sudden death <40

- 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 patient to absorb study
regimen/tolerate diarrhea

- Women who are currently pregnant/breast feeding

- Previous or current malignancies of other histologies the last year, with exception
of cervical carcinoma in situ & adequately treated basal cell or 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 < 4 weeks before start of study therapy unless
pt has recovered from all anticipated toxicities of chemo

- Last XRT < 4 weeks before start of study therapy, unless patient 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 < 4 weeks/incompletely healed surgical incision before starting study

- 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 weeks has
elapsed since last dose.

- Patients taking warfarin sodium

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Safety, tolerability, biologic activity, & pharmacokinetic profile of vandetanib when used in combo w etoposide

Outcome Time Frame:

6-month progression free survival

Safety Issue:


Principal Investigator

Annick Desjardins, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Duke University Health System


United States: Food and Drug Administration

Study ID:




Start Date:

February 2008

Completion Date:

May 2011

Related Keywords:

  • Gliosarcoma
  • Glioblastoma
  • Malignant Gliomas
  • Etopophos
  • Toposar
  • VePesid
  • Etoposide
  • Vandetanib
  • Zactima
  • ZD6474
  • VP-16
  • Brain Tumor
  • Recurring Malignant Brain Tumor
  • Gliosarcoma
  • Glioblastoma
  • Glioma
  • Malignant Glioma
  • GBM
  • Glioblastoma
  • Glioma
  • Gliosarcoma



Duke University Health SystemDurham, North Carolina  27705