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 ]

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 ]
  Hide Outcome Measure 11

Measure Type Secondary
Measure Title Elimination Half Life of Gefitinib (t1/2)
Measure Description No text entered.
Time Frame Week 2 of course 1  
Safety Issue No  

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.
PK Data was combined at each dose level accross strata (Stratum 1A, Stratum 1B, and Stratum 2); at Dose 250 mg/m^2 of Gefitinib accross strata, PK data from Phase-I patients was analysed earlier for the publication of the Phase-I trial. PK data for the Phase-II patients was analyzed separately for the Phase-II publication.

Reporting Groups
  Description
Dose 250 mg/m^2 of Gefitinib (Phase II, Brain Stem Gliomas) Brain Stem Glioma patients treated on the Phase-II trial. Seven patients were treated during Phase-I at the Phase-II dose, and thus eligible for the Phase-II trial, and included in this part of the report. Only 18 patients had samples for the PK evaluation.
Dose 250 mg/m^2 of Gefitinib (Phase I) This cohort includes all Phase-I patients treated at 250 mg/m^2 of Gefitinib regardless of diagnosis; that is, this group includes both brain stem gliomas and supratentorial malignant gliomas. Only six of 11 patients had adequate PK samples for the PK evaluation.
Dose 100 mg/m^2 of Gefitinib This cohort includes all Phase-I patients treated at 100 mg/m^2 of Gefitinib regardless of diagnosis; that is, this group includes both brain stem gliomas and supratentorial malignant gliomas. Eight (8) of 10 patients had adequate PK samples for the PK evaluation.
Dose 375 mg/m^2 of Gefitinib This cohort includes all Phase-I patients treated at 375 mg/m^2 of Gefitinib regardless of diagnosis; that is, this group includes both brain stem gliomas and supratentorial malignant gliomas. Eight of 12 patients had adequate PK samples for the PK evaluation.

Measured Values
    Dose 250 mg/m^2 of Gefitinib (Phase II, Brain Stem Gliomas)     Dose 250 mg/m^2 of Gefitinib (Phase I)     Dose 100 mg/m^2 of Gefitinib     Dose 375 mg/m^2 of Gefitinib  
Number of Participants Analyzed  
[units: participants]
  18     6     8     8  
Elimination Half Life of Gefitinib (t1/2)  
[units: hour]
Median ( Full Range )
  15.2  
  ( 9.2 to 24.9 )  
  17.6  
  ( 4.8 to 41.3 )  
  9.9  
  ( 1.8 to 19.9 )  
  10.4  
  ( 3.8 to 39.2 )  

No statistical analysis provided for Elimination Half Life of Gefitinib (t1/2)



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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