Ph I Zactima + Imatinib Mesylate & Hydroxyurea for Pts w Recurrent Malignant Glioma
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 enzyme inducing anti-epileptic drugs (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 recurrent malignant glioma (RMG) pts including radiographic response rate, 6-month progression free survival (PFS) rate & median PFS
|Study Design:||Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Phase I Study of Zactima (ZD6474) Plus Imatinib Mesylate and Hydroxyurea for Patients With Recurrent Malignant Glioma|
- To determine MTD & dose-limiting toxicity (DLT) & Zactima when combo w Imatinib mesylate & Hydroxyurea among pt w Recurrent MG [ Time Frame: 6 months ] [ Designated as safety issue: No ]
- To further assess safety & tolerability of Zactima & Imatinib mesylate & Hydroxyurea [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
|Study Start Date:||November 2007|
|Study Completion Date:||April 2009|
|Primary Completion Date:||March 2009 (Final data collection date for primary outcome measure)|
|Experimental: Zactima + Gleevec + Hydrea||
Drug: Zactima, Gleevec, Hydroxyurea
Pts will start treatment on day 1 of cycle 1 w Zactima, imatinib mesylate & hydroxyurea. All 3 agents administered in continuous daily, oral manner. Imatinib mesylate dose 400 mg/day for pts not on EIAEDs & 1000 mg/day for pts on EIAEDs based on previous studies demonstrating that pts on EIAEDs require significantly higher doses of imatinib mesylate & that such doses are safe & well tolerated. Dose of hydroxyurea 500 mg twice day. Dose level of Zactima will be increased in successive cohorts of pts as described below.
Cohorts of 3-6 pts will accrue at each dose level until MTD is defined. Each cohort will consist of a mini of 3 newly enrolled pts. Intra-patient dose escalation is not permitted. Cohorts may be expanded at any dose level for further elaboration of safety & pharmacokinetic parameters as required.
Treatment cycle is defined as daily administration of Zactima + imatinib mesylate & hydroxyurea for 28 days for purpose of scheduling evaluations.
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.
|United States, North Carolina|
|Duke University Health System|
|Durham, North Carolina, United States, 27710|
|Principal Investigator:||Annick Desjardins, MD, FRCPC||Duke University Health System|