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Sponsors and Collaborators: |
Duke University Novartis AstraZeneca |
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Information provided by: | Duke University |
ClinicalTrials.gov Identifier: | NCT00613054 |
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
Condition | Intervention | Phase |
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Glioblastoma Gliosarcoma |
Drug: Zactima, Gleevec, Hydroxyurea |
Phase II |
Study Type: | Interventional |
Study Design: | Treatment, Non-Randomized, Open Label, Active Control, Single Group Assignment, Efficacy Study |
Official Title: | Phase I Study of Zactima (ZD6474) Plus Imatinib Mesylate and Hydroxyurea for Patients With Recurrent Malignant Glioma |
Estimated Enrollment: | 48 |
Study Start Date: | November 2007 |
Estimated Study Completion Date: | November 2011 |
Estimated Primary Completion Date: | November 2009 (Final data collection date for primary outcome measure) |
Arms | Assigned Interventions |
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1: Experimental
Pts receiving EIAEDs
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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. |
2: Experimental
Pts not receiving EIAEDs
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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. |
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.
Ages Eligible for Study: | 18 Years and older |
Genders Eligible for Study: | Both |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
Exclusion Criteria:
Contact: David A. Reardon, MD | (919) 668-1409 | david.reardon@duke.edu |
Contact: Peggy Lyons | (919) 668-2447 | peggy.lyons@duke.edu |
United States, North Carolina | |
Duke University Health System | Recruiting |
Durham, North Carolina, United States, 27710 | |
Contact: David A. Reardon, MD 919-668-1409 david.reardon@duke.edu | |
Contact: Peggy Lyons (919) 668-2447 peggy.lyons@duke.edu |
Principal Investigator: | David A. Reardon, MD | Duke University Health System |
Responsible Party: | Duke University Health System ( David A. Reardon, MD ) |
Study ID Numbers: | 00000393 |
Study First Received: | January 29, 2008 |
Last Updated: | May 4, 2008 |
ClinicalTrials.gov Identifier: | NCT00613054 |
Health Authority: | United States: Food and Drug Administration |
Gliosarcoma GBM Brain tumor Zactima Gleevec Hydroxyurea Glioblastoma GBM |
Recurrent malignant glioma ZD6474 Malignant glioma Imatinib Droxia Hydrea Hydroxycarbamide Vandetanib |
Imatinib Neuroectodermal Tumors Brain Neoplasms Glioblastoma Astrocytoma Hydroxyurea |
Neoplasms, Germ Cell and Embryonal Neuroepithelioma Glioma Gliosarcoma Recurrence Neoplasms, Glandular and Epithelial |
Neoplasms by Histologic Type Antisickling Agents Molecular Mechanisms of Pharmacological Action Antineoplastic Agents Neoplasms, Nerve Tissue Hematologic Agents Enzyme Inhibitors |
Protein Kinase Inhibitors Pharmacologic Actions Neoplasms Therapeutic Uses Neoplasms, Neuroepithelial Nucleic Acid Synthesis Inhibitors |