Clinical Trial: Gefitinib and Radiation Therapy in Treating Children With Newly Diagnosed Gliomas

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

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

Brief 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 Summary:

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 stratifie
Sponsor: National Cancer Institute (NCI)

Current Primary Outcome:

  • Number of Participants in Phase I Stratum 1A With Dose-limiting Toxicities (DLT) Observed During the First 8 Weeks of Gefitinib Therapy [ Time Frame: Day 1 of gefitinib therapy to end of week 8 ]
    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.
  • Median Progression-free Survival in Newly Diagnosed Brain Stem Gliomas [ Time Frame: Assessed pre-radiation, every 8 weeks for 13 courses of therapy, and then every 12 weeks ]
    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
  • Median Survival in Newly Diagnosed Brain Stem Gliomas [ Time Frame: Assessed from the start of therapy until three years after initiation of gefitinib therapy ]
    Overall survival is defined as the interval from initiation of treatment to death or date of last contact for surviving patients


Original Primary Outcome:

Current Secondary Outcome:

  • 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 [ Time Frame: Baseline and two weeks post 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.
  • Change From Baseline in Volume Enhancing at Two Weeks After Completion of Radiation [ Time Frame: Baseline and two weeks post 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.
  • Change From Baseline in Diffusion Ratio at Two Weeks After Completion of Radiation [ Time Frame: Baseline and two weeks post 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.
  • Change From Baseline in Perfusion Ratio at Two Weeks After Completion of Radiation [ Time Frame: Baseline and two weeks post 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.
  • Mean Tumor to Gray Matter Ratio Measured at Baseline [ Time Frame: 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.
  • Mean Tumor to White Matter Ratio Measured at Baseline [ Time Frame: 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.
  • Peak Serum Concentration of Gefitinib (Cmax) [ Time Frame: Week 2 of course 1 ]
  • Elimination Half Life of Gefitinib (t1/2) [ Time Frame: Week 2 of course 1 ]
  • Clearance of Gefitinib (Cl) [ Time Frame: Week 2 of course 1 ]
  • Time of Maximum Clearance of Gefitinib (Tmax) [ Time Frame: Week 2 of course 1 ]
  • Gefitinib Area Under the Concentration Curve From 0-24 Hours (AUC) [ Time Frame: Week 2 of course 1 ]
  • Number of Patients With Epidermal Growth Factor Receptor (EGFR) Amplification [ Time Frame: Pre-treatment ]
    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.


Original Secondary Outcome:

Information By: National Cancer Institute (NCI)

Dates:
Date Received: August 5, 2002
Date Started: July 2002
Date Completion:
Last Updated: May 15, 2014
Last Verified: December 2012