Symptoms and General Pathology

All Conditions

Neoplasms

Nervous System Diseases

Rare Diseases

Recurrence

Glioma

Glioblastoma

Brain Neoplasms

Gliosarcoma

Astrocytoma

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Neuroepithelioma

Antineoplastic Agents

Antisickling Agents

All Drugs and Chemicals

Amino Acids

Hydroxyurea

Imatinib Mesylate

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

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.

Zactima, Gleevec, Hydroxyurea

Annick Desjardins, MD, FRCPC

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

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.

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

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

Novartis Pharmaceuticals

AstraZeneca

Annick Desjardins

Assistant Professor of Medicine

Anticonvulsants

Grade II Oligodendroglioma or oligoastrocytomas

Imatinib administered orally on daily. Imatinib is local irritant \& must be taken in sitting position; mini of 2hrs should be allowed between last drug intake \& going to bed. Imatinib doses 400mg/600mg administered once daily, whereas daily doses of 800mg/\> administered as equally divided dose taken twice day. Dose for imatinib: Pts not receiving p450-inducing antiepileptic drugs: 400 mg/day. Pts receiving p450-inducing antiepileptic drugs: 500 mg twice day. It is recommended that pts take their prescribed imatinib mesylate at same time that they take their prescribed hydroxyurea, however, 30-60min interval between agents is acceptable if required for practical/other compliance issues.

Hydroxyurea administered orally twice day. Dosing will begin on day 1 of cycle 1 \& continue daily. Drug is approximately 80 percent bioavailable. Dose will be 500mg twice day for all pts.

Imatinib Mesylate & Hydroxyurea

Primary objective:

* To evaluate activity of imatinib mesylate and hydroxyurea among patients with progressive/recurrent grade II low-grade glioma (LGG) as measured by 12-month progression free survival

Secondary objectives:

* To evaluate progression-free survival (PFS), overall survival and objective response rate among patients with progressive/recurrent grade II LGG treated with imatinib mesylate plus hydroxyurea
* To assess safety and tolerability of imatinib mesylate + hydroxyurea in this population

This is an open-label, single stage, uncontrolled, non-randomized Phase II study of continuous, daily doses of imatinib mesylate \& hydroxyurea in adult patients with progressive/recurrent Grade II low-grade glioma (LGG). The treatment cycle is defined as imatinib mesylate \& hydroxyurea administered daily for 28 days for purpose of scheduling evaluations. All patients who receive 1 or more doses of either imatinib mesylate or hydroxyurea will be evaluable for toxicity, whereas all patients who receive a minimum of 14 consecutive days of study regimen will be evaluable for response. Patients who discontinue therapy prior to receiving 14 consecutive days of study regimen will be regarded as ineligible for evaluation of response and will be replaced.

Phase II Imatinib + Hydroxyurea in Treatment of Patients With Recurrent/Progressive Grade II Low-Grade Glioma (LGG)

Phase II Study of Imatinib Mesylate Plus Hydroxyurea in the Treatment of Patients With Recurrent / Progressive Grade II Low-Grade Glioma

Percentage of participants surviving twelve months from the start of cycle 1 without progression of disease. PFS was defined as the time from the cycle 1 start date to the date of the first documented progression according to modified Macdonald criteria, or to death due to any cause.

Time in weeks from the start of cycle 1 to the date of first progression according to modified Macdonald criteria, or to death due to any cause. Patients alive who had not progressed as of the last follow-up had PFS censored at the last follow-up date. Median PFS was estimated using a Kaplan-Meier curve.

Time in weeks from the start of cycle 1 to date of death due to any cause. Patients alive at last follow-up are censored as of that follow-up date. Median OS was estimated using a Kaplan-Meier curve.

Number of participants with an objective response (complete response or partial response) based on modified Macdonald criteria.

The number of patients experiencing any serious adverse event or other (non-serious) adverse event during the study participation.

Duke University

All adverse events were gathered for the study using Common Terminology Criteria for Adverse Events (CTCAE) version 3.0, but were converted to CTCAE version 4.0 for entry into ClinicalTrials.gov.

Oligodendroglioma

Total

Age Continuous

Sex: Female, Male

12-month Progression Free Survival (PFS)

Median Progression-free Survival

Median overall survival was not estimable for either arm as not enough events of death occurred

Median Overall Survival (OS)

Objective Response Rate

Experienced any Serious Adverse Event

Experienced any (non-serious) Adverse Event

Safety and Tolerability of Gleevec + Hydroxyurea in Patients With Low-grade Gliomas

Overall Study

Meningioma

Neoplasms, Vascular Tissue

Meningeal Neoplasms

Central Nervous System Neoplasms

Nervous System Neoplasms

Brain Tumor, Adult

All patients receive imatinib mesylate and hydroxyurea orally on a daily, continuous basis. Dosing of imatinib mesylate is adjusted for patients who are also receiving p450-inducing anti-epileptic drugs.

Hydroxyurea is administered orally twice a day. The dose will be set at 500 mg twice a day for all patients. If vomiting occurs not additional trial medication should be taken that day in an effort to replace the material that has been vomited. It is recommended that patients take their prescribed hydroxyurea at the same time that they take their prescribed imatinib mesylate, however, a 30-60 minute interval between agents is acceptable, if required for practical or other compliance issues.

hydroxyurea

Imatinib administered orally on daily, continuous basis. Imatinib doses of 400mg/600mg administered once daily, whereas daily doses of 800mg/greater administered as equally divided dose taken twice day.

Dose for Imatinib:

Patients receiving p450-inducing antiepileptic drugs:500mg twice day Patients not receiving p450-inducing antiepileptic drugs:400mg/day.

If patients who were not on Cytochrome P450, family 3, subfamily A (CYP3A) enzyme-reducing anti-epileptic drug (EIAED) when originally enrolled must initiate CYP3A enzyme-inducing anti-epileptic drug while on study, study regimen will remain same for minimum of 2 wks before pt transitions to dosing as specified for patients on anti-epileptic drug. If patients originally enrolled must discontinue all EIAEDs while on study, in interest of patient safety, dosing of study regimen will transition to that of patients not on anti-epileptics immediately.

imatinib mesylate

David A. Reardon, MD

RATIONALE: Imatinib mesylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as hydroxyurea, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving imatinib mesylate together with hydroxyurea may kill more tumor cells.

PURPOSE: This phase II trial is studying how well giving imatinib mesylate together with hydroxyurea works in treating patients with recurrent or progressive meningioma.

OBJECTIVES:

Primary

* Evaluate the activity of imatinib mesylate and hydroxyurea, as measured by 6-month progression-free survival, in patients with recurrent or progressive meningioma.

Secondary

* Evaluate the progression-free survival (PFS)
* Overall survival (OS),
* Objective response rate among patients treated with this regimen.

OUTLINE: This is an open-label study.

Patients receive oral imatinib mesylate once or twice daily and oral hydroxyurea twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

PROJECTED ACCRUAL: A total of 21 patients will be accrued for this study.

Imatinib Mesylate and Hydroxyurea in Treating Patients With Recurrent or Progressive Meningioma

A Phase II Study of Imatinib Mesylate Plus Hydroxyurea in the Treatment of Patients With Recurrent/Progressive Meningioma

Percentage of participants surviving six months from the start of study treatment without progression of disease. PFS was defined as the time from the date of study treatment initiation to the date of the first documented progression according to the Macdonald criteria, or death due to any cause.

Time in months from the start of study treatment to the date of first progression according to Macdonald criteria, or to death due to any cause. Patients alive who had not progressed as of the last follow-up had PFS censored at the last follow-up date. Median PFS was estimated using a Kaplan-Meier curve.

Time in months from the start of study treatment to date of death due to any cause. Patients alive at last follow-up are censored as of that follow-up date. Median OS was estimated using a Kaplan-Meier curve.

Percentage of participants with an objective response (complete response or partial response). Per modified Macdonald criteria and assessed by MRI, complete response (CR) was the disappearance of all target lesions and partial response (PR) was a ≥50% decrease in the sum of the longest diameter of target lesions. Objective response = CR+PR.

National Cancer Institute (NCI)

Adverse Events were gathered in Common Terminology Criteria for Adverse Events (CTCAE) v. 3.0 and converted to CTCAE v. 4.0 for entry into ClinicalTrials.gov

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Ph I Zactima + Imatinib Mesylate & Hydroxyurea for Pts w Recurrent Malignant Glioma	NCT00613054	Glioblastoma Gliosarcoma	Zactima, Gleeve...	18 Years -	Duke University
Phase II Imatinib + Hydroxyurea in Treatment of Patients With Recurrent/Progressive Grade II Low-Grade Glioma (LGG)	NCT00615927	Glioblastoma Gliosarcoma	Imatinib Mesyla...	18 Years -	Duke University
Ph I Zactima + Imatinib Mesylate & Hydroxyurea for Pts w Recurrent Malignant Glioma	NCT00613054	Glioblastoma Gliosarcoma	Zactima, Gleeve...	18 Years -	Duke University
Imatinib Mesylate and Hydroxyurea in Treating Patients With Recurrent or Progressive Meningioma	NCT00354913	Glioblastoma Gliosarcoma	hydroxyurea imatinib mesyla...	18 Years -	Duke University

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