Phase I Study of Zactima (ZD6474) Plus Imatinib Mesylate and Hydroxyurea for Patients With Recurrent Malignant Glioma
vascular endothelial growth factor (VEGF) angiogenic & Phosphoinositide 3-kinase
inhibitor/Protein Kinase B (PI3K/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, epidermal growth factor receptor (EGFR) & platelet derived growth
factor(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 glioblastoma multiforme (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 maximum tolerated dose (MTD) of Zactima + imatinib mesylate in
order to evaluate anti-glioma potential of regimen.
Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
To determine MTD & dose-limiting toxicity (DLT) & Zactima when combo w Imatinib mesylate & Hydroxyurea among pt w Recurrent MG
Annick Desjardins, MD, FRCPC
Duke University Health System
United States: Food and Drug Administration
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