Ph I Dose Escalation Trial of Vandetanib in Combo w Etoposide for Malignant Gliomas

• Status: Completed
• Trial end date: 2011-05-01
• Target enrollment: 0
• Participant gender: All

Summary

Primary Objective: To determine maximum tolerated dose & dose limiting toxicity of vandetanib when combined with standard dosing of etoposide among patients with recurrent malignant glioma who are on & not on enzyme-inducing anti-epileptic drugs (EIAEDs) Secondary Objectives: To assess safety & tolerability of vandetanib + etoposide in this population; To evaluate pharmacokinetics of vandetanib among malignant glioma patients on & not on EIAEDs when combined with etoposide.

Exploratory Objective: To evaluate for evidence of anti-tumor activity of study regimen among recurrent malignant glioma patients 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
• Collaborator: AstraZeneca
• Treatments: Etoposide; Etoposide phosphate

Criteria

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 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 with unexplained sudden death <40 years

• 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 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 weeks has elapsed since last dose.

• Patients taking warfarin sodium