Gefitinib and Radiation Therapy in Treating Children With Newly Diagnosed Gliomas

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00042991
First received: August 5, 2002
Last updated: May 15, 2014
Last verified: December 2012
Results First Received: February 9, 2011  
Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Single Group Assignment;   Masking: Open Label;   Primary Purpose: Treatment
Conditions: 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
Interventions: Drug: gefitinib
Radiation: radiation therapy
Other: pharmacological study
Other: laboratory biomarker analysis

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Accrual to this study started with the first patient who enrolled on 07/01/2002 and ended with the last patient who enrolled on 05/31/2006. Nine institutions enrolled patients on the study.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
There was no randomization to the three strata, which were distinct based on diagnosis and the use of enzyme inducing anti-convulsants (EIACD).

Reporting Groups
  Description
Stratum 1A-100 mg/m^2 of Gefitinib + Radiation These are patients with newly diagnosed brain stem glioma who were treated at Dose 100 mg/m^2 of Gefitinib+Radiation, where Gefitinib was administered orally once daily.
Stratum 1A-250 mg/m^2 of Gefitinib + Radiation These are patients with newly diagnosed brain stem glioma who were treated at Dose 250 mg/m^2 of Gefitinib+Radiation, where Gefitinib was administered orally once daily.
Stratum 1A-375 mg/m^2 of Gefitinib + Radiation These are patients with newly diagnosed brain stem glioma who were treated at Dose 375 mg/m^2 of Gefitinib+Radiation, where Gefitinib was administered orally once daily.
Stratum-1B: 100 mg/m^2 of Gefitinib + Radiation These are patients with newly diagnosed, incompletely resected supertentorial malignant gliomas and NOT receiving enzyme inducing anticonvulsant drugs (EIACD), who were treated at Dose 100 mg/m^2 of Gefitinib+Radiation, where Gefitinib was administered orally once daily.
Stratum-1B: 250 mg/m^2 of Gefitinib + Radiation These are patients with newly diagnosed, incompletely resected supertentorial malignant gliomas and NOT receiving enzyme inducing anticonvulsant drugs (EIACD), who were treated at Dose 250 mg/m^2 of Gefitinib+Radiation, where Gefitinib was administered orally once daily.
Stratum-1B: 375 mg/m^2 of Gefitinib + Radiation These are patients with newly diagnosed, incompletely resected supertentorial malignant gliomas and NOT receiving enzyme inducing anticonvulsant drugs (EIACD), who were treated at Dose 375 mg/m^2 of Gefitinib+Radiation, where Gefitinib was administered orally once daily.
Stratum-2: 100 mg/m^2 of Gefitinib + Radiation + EIACD These are patients with newly diagnosed, incompletely resected supertentorial malignant gliomas and receiving enzyme inducing anticonvulsant drugs (EIACD), who were treated at Dose 100 mg/m^2 of Gefitinib+Radiation, where Gefitinib was administered orally once daily.

Participant Flow:   Overall Study
    Stratum 1A-100 mg/m^2 of Gefitinib + Radiation     Stratum 1A-250 mg/m^2 of Gefitinib + Radiation     Stratum 1A-375 mg/m^2 of Gefitinib + Radiation     Stratum-1B: 100 mg/m^2 of Gefitinib + Radiation     Stratum-1B: 250 mg/m^2 of Gefitinib + Radiation     Stratum-1B: 375 mg/m^2 of Gefitinib + Radiation     Stratum-2: 100 mg/m^2 of Gefitinib + Radiation + EIACD  
STARTED     6     43 [1]   7     2     3     5     3  
Phase-I Trial     6     7 [2]   7     2     3     5     3  
Phase-II Trial     0     36     0     0     0     0     0  
COMPLETED     0     3     1     0     0     0     1  
NOT COMPLETED     6     40     6     2     3     5     2  
Adverse Event                 1                 4                 2                 0                 0                 1                 0  
Withdrawal by Subject                 0                 7                 2                 0                 1                 0                 0  
Disease Progression                 5                 29                 2                 2                 1                 4                 2  
Alternative Therapy                 0                 0                 0                 0                 1                 0                 0  
[1] These 43 patients form the Phase-II cohort, seven contributing from the Phase-I trial.
[2] These seven patients contributed to both Phase-I and Phase-II objectives.



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
Stratum 1A-100 mg/m^2 of Gefitinib + Radiation These are patients with newly diagnosed brain stem glioma who were treated at Dose 100 mg/m^2 of Gefitinib+Radiation, where Gefitinib was administered orally once daily.
Stratum 1A-250 mg/m^2 of Gefitinib + Radiation These are patients with newly diagnosed brain stem glioma who were treated at Dose 250 mg/m^2 of Gefitinib+Radiation, where Gefitinib was administered orally once daily.
Stratum 1A-375 mg/m^2 of Gefitinib + Radiation These are patients with newly diagnosed brain stem glioma who were treated at Dose 375 mg/m^2 of Gefitinib+Radiation, where Gefitinib was administered orally once daily.
Stratum-1B: 100 mg/m^2 of Gefitinib + Radiation These are patients with newly diagnosed, incompletely resected supertentorial malignant gliomas and NOT receiving enzyme inducing anticonvulsant drugs (EIACD), who were treated at Dose 100 mg/m^2 of Gefitinib+Radiation, where Gefitinib was administered orally once daily.
Stratum-1B: 250 mg/m^2 of Gefitinib + Radiation These are patients with newly diagnosed, incompletely resected supertentorial malignant gliomas and NOT receiving enzyme inducing anticonvulsant drugs (EIACD), who were treated at Dose 250 mg/m^2 of Gefitinib+Radiation, where Gefitinib was administered orally once daily.
Stratum-1B: 375 mg/m^2 of Gefitinib + Radiation These are patients with newly diagnosed, incompletely resected supertentorial malignant gliomas and NOT receiving enzyme inducing anticonvulsant drugs (EIACD), who were treated at Dose 375 mg/m^2 of Gefitinib+Radiation, where Gefitinib was administered orally once daily.
Stratum-2: 100 mg/m^2 of Gefitinib + Radiation + EIACD These are patients with newly diagnosed, incompletely resected supertentorial malignant gliomas and receiving enzyme inducing anticonvulsant drugs (EIACD), who were treated at Dose 100 mg/m^2 of Gefitinib+Radiation, where Gefitinib was administered orally once daily.
Total Total of all reporting groups

Baseline Measures
    Stratum 1A-100 mg/m^2 of Gefitinib + Radiation     Stratum 1A-250 mg/m^2 of Gefitinib + Radiation     Stratum 1A-375 mg/m^2 of Gefitinib + Radiation     Stratum-1B: 100 mg/m^2 of Gefitinib + Radiation     Stratum-1B: 250 mg/m^2 of Gefitinib + Radiation     Stratum-1B: 375 mg/m^2 of Gefitinib + Radiation     Stratum-2: 100 mg/m^2 of Gefitinib + Radiation + EIACD     Total  
Number of Participants  
[units: participants]
  6     43     7     2     3     5     3     69  
Age  
[units: participants]
               
<=18 years     6     43     7     2     2     5     3     68  
Between 18 and 65 years     0     0     0     0     1     0     0     1  
>=65 years     0     0     0     0     0     0     0     0  
Age  
[units: years]
Mean ± Standard Deviation
  7.25  ± 2.92     8.02  ± 3.87     10.07  ± 4.71     9.17  ± 8.56     15.91  ± 5.61     11.69  ± 5.40     12.82  ± 2.37     9.01  ± 4.47  
Gender  
[units: participants]
               
Female     3     29     4     0     0     2     2     40  
Male     3     14     3     2     3     3     1     29  
Region of Enrollment  
[units: participants]
               
United States     6     43     7     2     3     5     3     69  



  Outcome Measures
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1.  Primary:   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 ]
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Measure Type Primary
Measure Title Number of Participants in Phase I Stratum 1A With Dose-limiting Toxicities (DLT) Observed During the First 8 Weeks of Gefitinib Therapy
Measure Description 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.
Time Frame Day 1 of gefitinib therapy to end of week 8  
Safety Issue Yes  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
This cohort includes only the patients who were enrolled and treated on Gefitinib+Radiation during the Phase I component of the trial, where the safety of Gefitinib was assedded at Dose Levels 100 mg/m^2, 250 mg/m^2, and 375 mg/m^2.

Reporting Groups
  Description
Stratum 1A-100 mg/m^2 of Gefitinib + Radiation These are patients with brain stem glioma who were treated during the Phase-I trial of Radiation+Dose 100 mg/m^2 of Gefitinib, where Gefitinib was administered orally once daily.
Stratum 1A-250 mg/m^2 of Gefitinib + Radiation These are patients with brain stem glioma who were treated during the Phase-I trial of Radiation+Dose 250 mg/m^2 of Gefitinib, where Gefitinib was administered orally once daily.
Stratum 1A-375 mg/m^2 of Gefitinib + Radiation These are patients with brain stem glioma who were treated during the Phase-I trial of Radiation+Dose 375 mg/m^2 of Gefitinib, where Gefitinib was administered orally once daily.

Measured Values
    Stratum 1A-100 mg/m^2 of Gefitinib + Radiation     Stratum 1A-250 mg/m^2 of Gefitinib + Radiation     Stratum 1A-375 mg/m^2 of Gefitinib + Radiation  
Number of Participants Analyzed  
[units: participants]
  6     7     7  
Number of Participants in Phase I Stratum 1A With Dose-limiting Toxicities (DLT) Observed During the First 8 Weeks of Gefitinib Therapy  
[units: Participants]
  2     0     1  

No statistical analysis provided for Number of Participants in Phase I Stratum 1A With Dose-limiting Toxicities (DLT) Observed During the First 8 Weeks of Gefitinib Therapy



2.  Primary:   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 ]

3.  Primary:   Median Survival in Newly Diagnosed Brain Stem Gliomas   [ Time Frame: Assessed from the start of therapy until three years after initiation of gefitinib therapy ]

4.  Secondary:   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 ]

5.  Secondary:   Change From Baseline in Volume Enhancing at Two Weeks After Completion of Radiation   [ Time Frame: Baseline and two weeks post completion of radiation ]

6.  Secondary:   Change From Baseline in Diffusion Ratio at Two Weeks After Completion of Radiation   [ Time Frame: Baseline and two weeks post completion of radiation ]

7.  Secondary:   Change From Baseline in Perfusion Ratio at Two Weeks After Completion of Radiation   [ Time Frame: Baseline and two weeks post completion of radiation ]

8.  Secondary:   Mean Tumor to Gray Matter Ratio Measured at Baseline   [ Time Frame: Baseline ]

9.  Secondary:   Mean Tumor to White Matter Ratio Measured at Baseline   [ Time Frame: Baseline ]

10.  Secondary:   Peak Serum Concentration of Gefitinib (Cmax)   [ Time Frame: Week 2 of course 1 ]

11.  Secondary:   Elimination Half Life of Gefitinib (t1/2)   [ Time Frame: Week 2 of course 1 ]

12.  Secondary:   Clearance of Gefitinib (Cl)   [ Time Frame: Week 2 of course 1 ]

13.  Secondary:   Time of Maximum Clearance of Gefitinib (Tmax)   [ Time Frame: Week 2 of course 1 ]

14.  Secondary:   Gefitinib Area Under the Concentration Curve From 0-24 Hours (AUC)   [ Time Frame: Week 2 of course 1 ]

15.  Secondary:   Number of Patients With Epidermal Growth Factor Receptor (EGFR) Amplification   [ Time Frame: Pre-treatment ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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