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

Condition(s) targeted: Glioblastoma; Gliosarcoma

Intervention: Zactima, Gleevec, Hydroxyurea (Drug)

Phase: Phase 2

Status: Recruiting

Sponsored by: Duke University

Official(s) and/or principal investigator(s):
David A. Reardon, MD, Principal Investigator, Affiliation: Duke University Health System

Overall contact:
David A. Reardon, MD, Phone: (919) 668-1409, Email: david.reardon@duke.edu

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 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 RMG pts including radiographic response rate, 6-month progression free survival rate & median PFS

Official title: Phase I Study of Zactima (ZD6474) Plus Imatinib Mesylate and Hydroxyurea for Patients With Recurrent Malignant Glioma

Study design: Allocation: Non-Randomized, Control: Active Control, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: To determine MTD & DLT & Zactima when combo w Imatinib mesylate & Hydroxyurea among pt w Recurrent MG

Secondary outcome: To further assess safety & tolerability of Zactima & Imatinib mesylate & Hydroxyurea

Detailed description: VEGF angiogenic & PI3-K/AKT mitogenic cascades are 2 upregulated cell signalling pathways in MG that contribute to several hallmark phenotypic features of these tumors. Regimen of Zactima + imatinib mesylate represents novel anti-glioma strategy because it targets 3 key mediators of dysregulated cell signalling involving VEGF & PI3K-AKT pathways including VEGFR, EGFR & PDGFR. Furthermore by combining Zactima w imatinib mesylate, VEGF & PI3-k/AKT pathways can potentially inhibit multiple mediators of each of these pathways. Regarding PI3-K/AKT signalling, regimen can inhibit activation of EGFR & PDGFR. Regarding VEGF signalling, regimen has potential to inhibit 3 components of VEGFR directed angiogenesis. 1st, Zactima can directly inhibit VEGFR activation. 2nd, both Zactima & imatinib mesylate can indirectly decrease activity of VEGF pathway by diminishing positive input from activated PI3-K/AKT signalling. 3rd, imatinib mesylate may inhibit PDGF-regulated pericyte maturation of tumor blood vessels.

We have previously demonstrated that regimen of imatinib mesylate + hydroxyurea is active regimen among recurrent GBM pts. Furthermore this activity appears substantially better than that reported for imatinib mesylate alone. Although mechanism of enhanced activity for imatinib mesylate when combo w hydroxyurea is unclear, it is logical to build upon combo of imatinib mesylate + hydroxyurea in subsequent studies rather than imatinib mesylate alone. Current study will therefore determine MTD of Zactima when combo w standard doses of imatinib mesylate & hydroxyurea among RMG pts. Ph II study will then be performed, incorporating MTD of Zactima + imatinib mesylate in order to evaluate anti-glioma potential of regimen.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

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

- KPS of >70

- ANC>1. 0 x 10 9/L

- Hgb>g/dL

- Platelets>100 x 10 9/L

- Serum creatinine<1. 5 x ULN/measured 24hr CrCl >50 mL/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 ULRR/CrCl <50mL/min

- K<4. 0 mmol/L despite supplementation; serum Ca/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 or which would jeopardize compliance w protocol

- Clinically significant cardiac event such as myocardial infarction; NYHA

classification of heart disease >2within 3mths 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 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 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 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 <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

David A. Reardon, MD, Phone: (919) 668-1409, Email: david.reardon@duke.edu

Duke University Health System, Durham, North Carolina 27710, United States; Recruiting
David A. Reardon, MD, Phone: 919-668-1409, Email: david.reardon@duke.edu
Peggy Lyons, Phone: (919) 668-2447, Email: peggy.lyons@duke.edu

The Preston Robert Tisch Brain Tumor Center at DUKE

Starting date: November 2007
Last updated: February 22, 2009