GlioblastomaPhase 1NCT00613054
Ph I Zactima + Imatinib Mesylate & Hydroxyurea for Pts w Recurrent Malignant Glioma
A Phase 1 study testing Zactima, Gleevec, Hydroxyurea in people with Glioblastoma and Gliosarcoma, run by Annick Desjardins at 1 site in United States.
Trial summary
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… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Glioblastoma, Gliosarcoma
- What is being tested?
- Zactima, Gleevec, Hydroxyurea
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 27 participants
- Where
- 1 siteUnited States
- Study dates
- Nov 2007to Apr 2009
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
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- Multifocal disease is eligible
- Age >18yrs
- Karnofsky Performance Status (KPS) of >70
- Absolute neutrophil count (ANC) > 1.0 x 10 9/L
- Hgb>g/dL
- Platelets>100 x 10 9/L
- Serum creatinine<1.5 x upper limit of normal (ULN)/measured 24hr creatinine clearance (CrCl) >50 milliliters/min/1.73m
- Life ≥12wks
- Written informed consent obtained prior to any screening procedures
Who cannot join
- Serum bilirubin >1.5x ULN of reference range
- Serum creatinine >1.5 x Upper Limit of the Reference Range (ULRR)/CrCl <50 milliliters/min
- K<4.0 mmol/L despite supplementation; serum Ca/Mg out of normal range despite supplementation
- alanine aminotransferase (ALT) or aspartate aminotransferase (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; New York Heart Association (NYHA) classification of heart disease >2 within 3 months 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
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- History of arrhythmia-symptomatic/requires treatment/asymptomatic sustained ventricular tachycardia. Atrial fibrillation, controlled on medication is not excluded
- Previous history of corrected QT interval (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 cytochrome P450 3A4 (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 radiation therapy (XRT) <4wks before start of study therapy, unless pt has recovered from all anticipated toxicities of XRT
- Any unresolved toxicity > Common Terminology Criteria (CTC) grade 1 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
Trial locations and contacts
1 site in 1 country.
United States1 site
Duke University Health System
Durham, North Carolina, 27710
About this study
Official title: Phase I Study of Zactima (ZD6474) Plus Imatinib Mesylate and Hydroxyurea for Patients With 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
Read the detailed description
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.
- Conditions
- Glioblastoma, Gliosarcoma
- Being tested
- Zactima, Gleevec, Hydroxyurea
- Keywords
- GBM, Brain tumor, Zactima, Gleevec, Hydroxyurea, Glioblastoma, Gliosarcoma, Recurrent malignant glioma, ZD6474, Malignant glioma, Imatinib, Droxia, Hydrea, Hydroxycarbamide, Vandetanib
- Medical subject headings
- Glioblastoma, Gliosarcoma, Brain Neoplasms, Glioma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Zactima, Gleevec, HydroxyureaDrug
Also called Zactima-ZD6474-Vandetanib, Gleevec-Imatinib mesylate, Hydroxyurea-Droxia-Hydrea-Hydroxycarbamide
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.
| Study group | Role | What they receive |
|---|---|---|
| Zactima + Gleevec + Hydrea | Experimental | Not described Receives: Drug: Zactima, Gleevec, Hydroxyurea |
What is being measured
The primary outcome is the main question the study is designed to answer.
To determine MTD & dose-limiting toxicity (DLT) & Zactima when combo w Imatinib mesylate & Hydroxyurea among pt w Recurrent MG
Measured: 6 months
Secondary outcomes (1)
To further assess safety & tolerability of Zactima & Imatinib mesylate & Hydroxyurea
Measured: 6 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 Feb 2008 (estimated)
- Study startNov 2007
- Primary completionMar 2009
- Study completionApr 2009
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for GlioblastomaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 27 participants (actual)
Sponsor and investigators
- Lead sponsor
- Annick Desjardins
- Sponsor type
- University, hospital or other
- Collaborators
- Novartis Pharmaceuticals, AstraZeneca
- Responsible party
- Sponsor-investigator, Annick Desjardins, Duke University
- Investigators
- Annick Desjardins, MD, FRCPC, Principal investigator, Duke Health
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00613054
- Sponsor's protocol ID
- Pro00000393
- Status last verified
- Dec 2012
- First submitted
- 29 Jan 2008
- Last updated
- 5 Dec 2012
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 5 Dec 2012. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase I Study of Zactima (ZD6474) Plus Imatinib Mesylate and Hydroxyurea for Patients With Recurrent Malignant Glioma
- ClinicalTrials.gov ID
- NCT00613054
- Acronym / sponsor ID
- Pro00000393
- Conditions
- Glioblastoma, Gliosarcoma
- Keywords
- GBM, Brain tumor, Zactima, Gleevec, Hydroxyurea, Glioblastoma, Gliosarcoma, Recurrent malignant glioma
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 27 participants (actual)
- Lead sponsor
- Annick DesjardinsUniversity, hospital or other
- Collaborators
- Novartis Pharmaceuticals, AstraZeneca
- Study start
- Nov 2007
- Primary completion
- Mar 2009 (actual)
- Study completion
- Apr 2009 (actual)
- First posted
- 12 Feb 2008 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
Detailed description
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Zactima + Gleevec + Hydrea | Experimental | Drug: Zactima, Gleevec, Hydroxyurea |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (15 listed)
- 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
Key exclusion criteria (24 listed)
- Serum bilirubin >1.5x ULN of reference range
- Serum creatinine >1.5 x Upper Limit of the Reference Range (ULRR)/CrCl <50 milliliters/min
- K<4.0 mmol/L despite supplementation; serum Ca/Mg out of normal range despite supplementation
- alanine aminotransferase (ALT) or aspartate aminotransferase (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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Zactima, Gleevec, HydroxyureaAlso: Zactima-ZD6474-Vandetanib, Gleevec-Imatinib mesylate, Hydroxyurea-Droxia-Hydrea-HydroxycarbamidePts 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. | Drug | Zactima + Gleevec + Hydrea |
Primary outcome
To determine MTD & dose-limiting toxicity (DLT) & Zactima when combo w Imatinib mesylate & Hydroxyurea among pt w Recurrent MG
Time frame: 6 months
1 secondary outcome
To further assess safety & tolerability of Zactima & Imatinib mesylate & Hydroxyurea
Time frame: 6 months
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 5 Dec 2012.
- The Preston Robert Tisch Brain Tumor Center at DUKELink provided by the sponsor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Annick Desjardins, MD, FRCPC principal investigator
Duke Health
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Zactima, Gleevec, Hydroxyurea in people with Glioblastoma and Gliosarcoma, run by Annick Desjardins at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 15 inclusion and 24 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 5 Dec 2012. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
To determine MTD & dose-limiting toxicity (DLT) & Zactima when combo w Imatinib mesylate & Hydroxyurea among pt w Recurrent MG (time frame: 6 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Dec 2012.