Gefitinib (Iressa) and Radiation Therapy in Treating Children With Newly Diagnosed Gliomas

This study has been completed.
Sponsor:
Collaborator:
Information provided by:
Pediatric Brain Tumor Consortium
ClinicalTrials.gov Identifier:
NCT00042991
First received: August 5, 2002
Last updated: June 13, 2011
Last verified: June 2011
  Purpose

RATIONALE: 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.

PURPOSE: This phase I/II trial is studying how well giving gefitinib together with radiation therapy works in treating children with newly diagnosed glioma.


Condition Intervention Phase
Brain and Central Nervous System Tumors
Drug: Gefitinib
Radiation: Local Irradiation
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I/II Trial Of ZD1839 (Iressa) 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

Resource links provided by NLM:


Further study details as provided by Pediatric Brain Tumor Consortium:

Primary Outcome Measures:
  • 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 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    Overall survival is defined as the interval from initiation of treatment to death or date of last contact for surviving patients


Secondary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
  • Elimination Half Life of Gefitinib (t1/2) [ Time Frame: Week 2 of course 1 ] [ Designated as safety issue: No ]
  • Clearance of Gefitinib (Cl) [ Time Frame: Week 2 of course 1 ] [ Designated as safety issue: No ]
  • Time of Maximum Clearance of Gefitinib (Tmax) [ Time Frame: Week 2 of course 1 ] [ Designated as safety issue: No ]
  • Gefitinib Area Under the Concentration Curve From 0-24 Hours (AUC) [ Time Frame: Week 2 of course 1 ] [ Designated as safety issue: No ]
  • Number of Patients With Epidermal Growth Factor Receptor (EGFR) Amplification [ Time Frame: Pre-treatment ] [ Designated as safety issue: No ]
    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.


Enrollment: 69
Study Start Date: August 2002
Study Completion Date: March 2010
Primary Completion Date: February 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Radiation + Gefitinib Drug: Gefitinib
  • Phase I: Study participants will receive 75, 100, 250, 375, 500, 650, or 850 mg/m2 gefitinib orally once daily for 4 weeks (1 course). In the absence of disease progression, treatment repeats every 4 weeks for up to 13 courses (1 year).
  • Phase II: Study participants receive 250 mg/m2 of gefitinib orally once daily for four weeks (one course). In the absence of disease progression or toxicity, treatment will continue for up to 13 courses (1 year).
Other Names:
  • ZD1839
  • Iressa
  • NSC 715055
  • IND# 61187
Radiation: Local Irradiation
Study subjects will receive local irradiation using conventional or conformal, volume-based delivery techniques. 180 cGy fractions will be used for all target volumes. Radiation will be given once daily, 5 days/week for six weeks to a total dose of 5580 cGy.

Detailed Description:

OBJECTIVES:

  • Determine the safety and maximum tolerated dose of gefitinib when combined with brain irradiation in children with newly diagnosed brain stem gliomas (BSG) or incompletely resected supratentorial malignant gliomas (STMG) who are not receiving concurrent enzyme-inducing anticonvulsant drugs (EIACDs). (Phase I closed to accrual effective 10/27/2003).
  • Determine the safety of this regimen in children with newly diagnosed incompletely resected supratentorial malignant gliomas who are receiving concurrent enzyme-inducing anticonvulsant drugs. (Phase I closed to accrual effective 10/27/2003).
  • Determine the safety and efficacy of this regimen in children with newly diagnosed poor-prognosis brain stem glioma.(Phase II)
  • Correlate the hemodynamic Magnetic Resonance Imaging (MRI) parameters to metabolic fludeoxyglucose F 18-positron emission tomography scanning with clinical response or progression in patients treated with this regimen. (Phase II)
  • Determine the pharmacokinetics of gefitinib in these patients for both Phase-I and Phase-II.

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.

  Eligibility

Ages Eligible for Study:   3 Years to 21 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

DISEASE CHARACTERISTICS:

  • Diagnosis of 1 of the following:

    • Newly diagnosed non-disseminated diffuse intrinsic brain stem glioma (BSG)
    • Newly diagnosed incompletely resected supratentorial malignant glioma, including anaplastic astrocytoma, glioblastoma multiforme, or other high-grade gliomas (Phase I closed to accrual effective 10/27/2003)

      • Must have residual tumor by postoperative MRI or CT scan
  • Bone marrow involvement by disease allowed
  • No disseminated disease
  • No spinal disease requiring radiotherapy
  • No evidence of intratumoral hemorrhage

PATIENT CHARACTERISTICS:

Age

  • 3 to 21

Performance status

  • Karnofsky 50-100% OR
  • Lansky 50-100%

Life expectancy

  • Not specified

Hematopoietic

  • Absolute neutrophil count greater than 1,000/mm^3 *
  • Platelet count greater than 100,000/mm^3 *
  • Hemoglobin greater than 8 g/dL (transfusion allowed) NOTE: *Transfusion independent

Hepatic

  • Bilirubin no greater than 1.5 times normal
  • ALT less than 3 times normal
  • Albumin at least 2 g/dL
  • No significant hepatic disease

Renal

  • Creatinine less than 2 times normal OR
  • Glomerular filtration rate greater than 70 mL/min
  • No significant renal disease

Cardiovascular

  • No significant cardiac disease
  • No deep venous or arterial thrombosis within the past 6 weeks

Pulmonary

  • No significant pulmonary disease

Other

  • No uncontrolled infection
  • No significant gastrointestinal disease
  • No significant psychiatric disease
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception during and for at least 6 months after study participation

PRIOR CONCURRENT THERAPY:

Biologic therapy

  • More than 2 weeks since prior colony-stimulating growth factors (e.g., filgrastim [G-CSF], sargramostim [GM-CSF], or epoetin alfa)
  • No prior bone marrow transplantation

Chemotherapy

  • No prior chemotherapy

Endocrine therapy

  • Concurrent corticosteroids allowed if receiving a stable or decreasing dose for at least 1 week before study entry
  • No concurrent tamoxifen

Radiotherapy

  • See Disease Characteristics
  • No prior radiotherapy

Surgery

  • See Disease Characteristics
  • No concurrent neurosurgical procedures for reasons other than progression (e.g., onset of hydrocephalus)

Other

  • No prior gefitinib
  • No other concurrent anticancer or experimental drug therapy
  • No concurrent drugs with known corneal toxicity (e.g., chlorpromazine, amiodarone, or chloroquine)
  • No concurrent enzyme-inducing anticonvulsant drugs for patients with brain stem glioma
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00042991

Locations
United States, California
UCSF Comprehensive Cancer Center
San Francisco, California, United States, 94115
United States, District of Columbia
Children's National Medical Center
Washington, District of Columbia, United States, 20010-2970
United States, Illinois
Children's Memorial Hospital - Chicago
Chicago, Illinois, United States, 60614
United States, Massachusetts
Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute
Boston, Massachusetts, United States, 02115
United States, North Carolina
Duke Comprehensive Cancer Center
Durham, North Carolina, United States, 27710
United States, Pennsylvania
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States, 19104-4318
Children's Hospital of Pittsburgh
Pittsburgh, Pennsylvania, United States, 15213
United States, Tennessee
St. Jude Children's Research Hospital
Memphis, Tennessee, United States, 38105
United States, Texas
Texas Children's Cancer Center and Hematology Service at Texas Children's Hospital
Houston, Texas, United States, 77030-2399
United States, Washington
Children's Hospital and Regional Medical Center - Seattle
Seattle, Washington, United States, 98105
Sponsors and Collaborators
Pediatric Brain Tumor Consortium
Investigators
Study Chair: Jeffrey R. Geyer, MD Seattle Children's Hospital
  More Information

Additional Information:
No publications provided

Responsible Party: James M. Boyett, Executive Director Operations and Biostatistics Center for the PBTC, Pediatric Brain Tumor Consortium (PBTC)
ClinicalTrials.gov Identifier: NCT00042991     History of Changes
Other Study ID Numbers: CDR0000069490, PBTC-007, 715055
Study First Received: August 5, 2002
Results First Received: February 9, 2011
Last Updated: June 13, 2011
Health Authority: United States: Food and Drug Administration

Keywords provided by Pediatric Brain Tumor Consortium:
untreated childhood brain stem glioma supratentorial malignant glioma

Additional relevant MeSH terms:
Glioma
Nervous System Neoplasms
Central Nervous System Neoplasms
Brain Stem Neoplasms
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Neoplasms by Site
Nervous System Diseases
Infratentorial Neoplasms
Brain Neoplasms
Brain Diseases
Central Nervous System Diseases
Gefitinib
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on April 15, 2014