Gefitinib and Radiation Therapy in Treating Children With Newly Diagnosed Gliomas
Condition: 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
MeSH terms: Glioblastoma; Glioma; Astrocytoma; Gliosarcoma; Oligodendroglioma; Neoplasms, Neuroepithelial
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      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: 
      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.
    

Intervention name(s): gefitinib; radiation therapy; pharmacological study; laboratory biomarker analysis
Intervention type(s): Drug; Radiation; Other; Other
Intervention description(s): Given orally; Undergo standard brain irradiation; Correlative studies; Correlative studies
Other intervention name(s): Iressa; irradiation; radiotherapy; therapy, radiation; pharmacological studies
Intervention MeSH terms: Gefitinib
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment