Gefitinib and Radiation Therapy in Treating Children With Newly Diagnosed Gliomas

Study Overview
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Brief Summary
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Biological therapies such as gefitinib may interfere with the growth of the tumor cells and may make the tumor cells more sensitive to radiation therapy. This phase I/II trial is studying how well giving gefitinib together with radiation therapy works in treating children with newly diagnosed glioma.

Detailed Description
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PRIMARY OBJECTIVES: I. To define the safety of gefitinib administered in conjunction with irradiation in children with newly diagnosed non-disseminated diffuse intrinsic brainstem gliomas and newly diagnosed incompletely resected supratentorial malignant gliomas (STMG) not receiving enzyme inducing anticonvulsant drugs (EIACDs). II. To define the safety of gefitinib in children with newly diagnosed, incompletely resected STMG receiving EIACDs. III. To assess the safety and efficacy of gefitinib given with radiation therapy in children newly diagnosed with a brainstem glioma as measured by progression-free survival and to estimate the survival distribution. SECONDARY OBJECTIVES: I. To compare hemodynamic magnetic resonance (MR) parameters to metabolic fludeoxyglucose F 18 (FDG)-positron emission tomography (PET) scanning and correlate both with clinical response or progression in this population. II. To characterize the expression of ErbB1 receptors in tissue from STMG patients using immunohistochemistry and western blot assays. III. To characterize the pharmacokinetics of gefitinib in the above patient groups and determine the effects of EIACD on the pharmacokinetics. IV. To explore the pharmacogenetic polymorphisms for gefitinib (e.g., CYP3A4/5 and BCRP) and relate them to gefitinib pharmacokinetics and pharmacodynamics (phenotype-genotype). OUTLINE: This is a multicenter, dose-escalation study of gefitinib (Phase I closed to accrual effective 10/27/2003). Patients are stratified according to the following: Stratum 1A: Intrinsic brain stem glioma; not receiving concurrent enzyme-inducing anticonvulsant drugs (EIACDs) Stratum 1B: Incompletely resected supratentorial malignant gliomas (STMG); not receiving concurrent EIACDs Stratum 2: Incompletely resected STMG; receiving concurrent EIACDs. Phase I portion (patients in strata 1A, 1B, and 2) (phase I closed to accrual effective 10/27/2003): Patients receive oral gefitinib once daily. Treatment repeats every 4 weeks for 13 courses (1 year). Patients also receive standard brain irradiation once daily, 5 days a week, for 6 weeks beginning concurrently with initiation of the first course of gefitinib. Treatment continues in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of gefitinib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity. Phase II portion (patients in stratum 1A): Once the MTD or the recommended Phase-II dose is determined, additional patients who have newly diagnosed brain stem gliomas (BSG) are treated at the MTD or the recommended Phase-II dose. Patients are followed for three months after the last protocol treatment for those enrolled strictly on the phase I component. Patients contributing to the phase II portion are followed until the earliest of date of death or three years after initiation of protocol therapy. PROJECTED ACCRUAL: Considering the seven dose levels to be investigated in three strata, where each dose level can accrue up to six patients, a total of 126 patients (42 for each strata) may be accrued for this study within 2 years. (Phase I closed to accrual effective 10/27/2003). A total of 40 patients including the patients treated at the maximum tolerated dose or the recommended Phase-II dose during Phase I will be accrued for phase II of this study within 10 months.

Official Title
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Phase I/II Trial of Gefitinib and Radiation in Pediatric Patients Newly Diagnosed With Brain Stem Tumors or Incompletely Resected Supratentorial Malignant Gliomas With Phase II Limited to Brain Stem Tumors

Conditions
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Untreated Childhood Anaplastic Astrocytoma, Untreated Childhood Anaplastic Oligodendroglioma, Untreated Childhood Brain Stem Glioma, Untreated Childhood Giant Cell Glioblastoma, Untreated Childhood Glioblastoma, Untreated Childhood Gliomatosis Cerebri, Untreated Childhood Gliosarcoma, Untreated Childhood Oligodendroglioma

Intervention / Treatment
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* Drug: gefitinib
* Radiation: radiation therapy
* Other: pharmacological study
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Tumor: Phase I: newly diagnosed non-disseminated diffuse intrinsic brainstem tumor or newly diagnosed (diagnostic scan must be within 4 weeks prior to treatment initiation), incompletely resected supratentorial malignant glioma (anaplastic astrocytoma, glioblastoma multiforme or other high-grade glioma) (STMG); the STMG group must have residual tumor evident on postoperative MRI or CT Phase II: only newly diagnosed non-disseminated diffuse intrinsic brain stem glioma patients are eligible Performance status: Karnofsky or Lansky >= 50% assessed within two weeks prior to registration Prior/concurrent therapy: Chemotherapy: no prior therapy allowed, including prior gefitinib treatment Radiation therapy (XRT): no prior therapy allowed Bone marrow transplant: none prior Anti-convulsants: patients with brain stem glioma (BSG) receiving EIACD will not be eligible; patients with STMG will be eligible for this study even if they are receiving enzyme inducting anti-convulsant drugs (EIACD) and will be stratified by use of EIACDs Growth factors: off all colony forming growth factor(s) > 2 weeks prior to registration (G-CSF, GM-CSF, erythropoietin) ANC > 1,000/ul Platelets > 100,000/ul (transfusion independent) Hemoglobin > 8g/dl (may be transfused) Patients may have bone marrow involvement by disease Creatinine < 2 x normal for age or GFR > 70 ml/min/1.73m^2 Bilirubin < 1.5 x normal institutional normal for age SGPT (ALT) < 3 x institutional normal for age Pregnant and/or lactating patients are excluded; patients of childbearing potential should not become pregnant and should not father a child during treatment with gefitinib; pregnancy tests must be obtained in girls who are post-menarchal; males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method Signed informed consent according to institutional guidelines must be obtained prior to study entry Exclusion Criteria: Patients with evidence of intramural hemorrhage on a scan obtained prior to enrollment or after enrollment, before treatment Patients with BSG must not be taking enzyme-inducing anticonvulsant drugs Patient must not be receiving any other anticancer or experimental drug therapy Patient must have no uncontrolled infection Patients with significant cardiac, hepatic, gastrointestinal, renal, pulmonary, or psychiatric disease are ineligible; patients with deep venous or arterial thrombosis within 6 weeks of study entry are ineligible Patients with disseminated disease are not permitted Patients with spinal disease requiring craniospinal radiation are not eligible Patients with completely resected supratentorial malignant gliomas patients are ineligible

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (gefitinib and radiation therapy)<br>Phase I portion: Patients receive oral gefitinib once daily. Treatment repeats every 4 weeks for 13 courses (1 year). Patients also receive standard brain irradiation once daily, 5 days a week, for 6 weeks beginning concurrently with initiation of the first course of gefitinib. Treatment continues in the absence of disease progression or unacceptable toxicity. Phase II portion: Once the MTD or the recommended Phase-II dose is determined, additional patients who have newly diagnosed BSG are treated at the MTD or the recommended Phase-II dose. | Drug: gefitinib<br>* Given orally<br>* Other names: Iressa;Radiation: radiation therapy<br>* Undergo standard brain irradiation<br>* Other names: therapy, radiation;Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants in Phase I Stratum 1A With Dose-limiting Toxicities (DLT) Observed During the First 8 Weeks of Gefitinib Therapy | The dose limiting toxicity (DLT) analysis population consists of stratum 1A phase I participants who developed DLT during the maximum tolerated dose (MTD) estimation period (course 1 and 2) or who completed the MTD estimation period without DLTs. DLTs observed during courses 1 and 2 were used to estimate the MTD based on the tradional 3+3 design, where a dose is considered a safe dose only when 0 out of 3, or at most 1 out of 6 patients has DLTs. When two or more patients in a group of 2 to 6 patients had DLTs, then that dose level was considered to be too toxic. | Day 1 of gefitinib therapy to end of week 8 | 
| Median Progression-free Survival in Newly Diagnosed Brain Stem Gliomas | Progression-free survival is defined as the interval from intiation of treatment to the earliest of disease progression (tumor increase of 25% over baseline tumor measurement; appearance of new lesion(s); or progressive/worsening neurlogical status) or death for patients who failed or to the last date of follow-up for patients without failure | Assessed pre-radiation, every 8 weeks for 13 courses of therapy, and then every 12 weeks | 
| Median Survival in Newly Diagnosed Brain Stem Gliomas | Overall survival is defined as the interval from initiation of treatment to death or date of last contact for surviving patients | Assessed from the start of therapy until three years after initiation of gefitinib therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Tumor Volume Measured on Fluid Attenuated Inversion Recovery (FLAIR) Imaging at Before the Protocol Therapy Started and at Two Weeks After Completion of Radiation | This study attempted to investigate in an exploratory manner the effect of treatment on changes in various neuroimaging variables. In this particular objective, the study aimed to investigate how radiation+gefitinib affect the tumor volume. Tumor volume is measured using Fluid Attenuated Inversion Recovery (FLAIR) before and after the radiation therapy. | Baseline and two weeks post completion of radiation | 
| Change From Baseline in Volume Enhancing at Two Weeks After Completion of Radiation | This study attempted to investigate in an exploratory manner the effect of treatment on changes in various neuroimaging variables. Neuroimaging changes may have some association with outcome (response,survival, etc.). Volume enhancing is one parameter obtained from standard magnetic resonance imaging (MRI) studies of the brain. | Baseline and two weeks post completion of radiation | 
| Change From Baseline in Diffusion Ratio at Two Weeks After Completion of Radiation | This study attempted to investigate in an exploratory manner the effect of treatment on changes in various neuroimaging variables. Neuroimaging changes may have some association with outcome (response,survival, etc.). Diffusion ratio is one parameter obtained from standard magnetic resonance imaging (MRI) studies of the brain. | Baseline and two weeks post completion of radiation | 
| Change From Baseline in Perfusion Ratio at Two Weeks After Completion of Radiation | This study attempted to investigate in an exploratory manner the effect of treatment on changes in various neuroimaging variables. Neuroimaging changes may have some association with outcome (response,survival, etc.). Perfusion ratio is one parameter obtained from standard magnetic resonance imaging (MRI) studies of the brain. | Baseline and two weeks post completion of radiation | 
| Mean Tumor to Gray Matter Ratio Measured at Baseline | This study attempts to characterize neuroimaging parameters from positron emission tomography. For each patient, the axial image through the tumor containing the maximum activity per pixel corresponding to the highest FluoroDeoxyGlucose (FDG) uptake was identified and a region of interest (ROI) was drawn based on the FDG definition of the tumor. The mean pixel values within the tumor ROI were normalized by those for normal gray matter to provide ratios of tumor/gray matter. Each patient has a mean tumor to gray matter ratio value and the median of these values across patients is reported. | Baseline | 
| Mean Tumor to White Matter Ratio Measured at Baseline | This study attempts to characterize neuroimaging parameters from positron emission tomography. For each patient, the axial image through the tumor containing the maximum activity per pixel corresponding to the highest FluoroDeoxyGlucose (FDG) uptake was identified and a region of interest (ROI) was drawn based on the FDG definition of the tumor. The mean pixel values within the tumor ROI were normalized by those for normal white matter to provide ratios of tumor/gray matter. Each patient has a mean tumor to white matter ratio value and the median of these values across patients is reported. | Baseline | 
| Peak Serum Concentration of Gefitinib (Cmax) |  | Week 2 of course 1 | 
| Elimination Half Life of Gefitinib (t1/2) |  | Week 2 of course 1 | 
| Clearance of Gefitinib (Cl) |  | Week 2 of course 1 | 
| Time of Maximum Clearance of Gefitinib (Tmax) |  | Week 2 of course 1 | 
| Gefitinib Area Under the Concentration Curve From 0-24 Hours (AUC) |  | Week 2 of course 1 | 
| Number of Patients With Epidermal Growth Factor Receptor (EGFR) Amplification | Epidermal growth factor receptor (EFGR) is a protein found on the surface of cells to which epidermal growth factor (EGF) binds. When EGF attaches to EGFR, it activates the enzyme tyrosine kinase, triggering reactions that cause the cells to grow and multiply. | Pre-treatment |