Clinical Trial Finder

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

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.

Arms

Experimental: Treatment (gefitinib and radiation therapy)

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.

Interventions

Drug: - gefitinib

Given orally

Radiation: - radiation therapy

Undergo standard brain irradiation

Other: - pharmacological study

Correlative studies

Other: - laboratory biomarker analysis

Correlative studies