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
Conditions
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 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.
Interventions
DRUGgefitinib
Given orally
RADIATIONradiation therapy
Undergo standard brain irradiation
OTHERpharmacological study
Correlative studies
OTHERlaboratory biomarker analysis
Correlative studies
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
3 Years to 21 Years
Healthy volunteers
No
Inclusion criteria
* Tumor: * Phase I: newly diagnosed non-disseminated diffuse intrinsic brainstem tumor or newly diagnosed (diagnostic scan must be within 4 weeks prior to treatment initiation), incompletely resected supratentorial malignant glioma (anaplastic astrocytoma, glioblastoma multiforme or other high-grade glioma) (STMG); the STMG group must have residual tumor evident on postoperative MRI or CT * Phase II: only newly diagnosed non-disseminated diffuse intrinsic brain stem glioma patients are eligible * Performance status: Karnofsky or Lansky \>= 50% assessed within two weeks prior to registration * Prior/concurrent therapy: * Chemotherapy: no prior therapy allowed, including prior gefitinib treatment * Radiation therapy (XRT): no prior therapy allowed * Bone marrow transplant: none prior * Anti-convulsants: patients with brain stem glioma (BSG) receiving EIACD will not be eligible; patients with STMG will be eligible for this study even if they are receiving enzyme inducting anti-convulsant drugs (EIACD) and will be stratified by use of EIACDs * Growth factors: off all colony forming growth factor(s) \> 2 weeks prior to registration (G-CSF, GM-CSF, erythropoietin) * ANC \> 1,000/ul * Platelets \> 100,000/ul (transfusion independent) * Hemoglobin \> 8g/dl (may be transfused) * Patients may have bone marrow involvement by disease * Creatinine \< 2 x normal for age or GFR \> 70 ml/min/1.73m\^2 * Bilirubin \< 1.5 x normal institutional normal for age * SGPT (ALT) \< 3 x institutional normal for age * Pregnant and/or lactating patients are excluded; patients of childbearing potential should not become pregnant and should not father a child during treatment with gefitinib; pregnancy tests must be obtained in girls who are post-menarchal; males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method * Signed informed consent according to institutional guidelines must be obtained prior to study entry
Exclusion criteria
* Patients with evidence of intramural hemorrhage on a scan obtained prior to enrollment or after enrollment, before treatment * Patients with BSG must not be taking enzyme-inducing anticonvulsant drugs * Patient must not be receiving any other anticancer or experimental drug therapy * Patient must have no uncontrolled infection * Patients with significant cardiac, hepatic, gastrointestinal, renal, pulmonary, or psychiatric disease are ineligible; patients with deep venous or arterial thrombosis within 6 weeks of study entry are ineligible * Patients with disseminated disease are not permitted * Patients with spinal disease requiring craniospinal radiation are not eligible * Patients with completely resected supratentorial malignant gliomas patients are ineligible
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants in Phase I Stratum 1A With Dose-limiting Toxicities (DLT) Observed During the First 8 Weeks of Gefitinib Therapy | 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 | 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 | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Perfusion Ratio at Two Weeks After Completion of Radiation | 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 | 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 | 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) | Week 2 of course 1 | — |
| 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 | 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. |
| Clearance of Gefitinib (Cl) | Week 2 of course 1 | — |
| Time of Maximum Clearance of Gefitinib (Tmax) | Week 2 of course 1 | — |
| Gefitinib Area Under the Concentration Curve From 0-24 Hours (AUC) | Week 2 of course 1 | — |
| Number of Patients With Epidermal Growth Factor Receptor (EGFR) Amplification | 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. |
| Elimination Half Life of Gefitinib (t1/2) | Week 2 of course 1 | — |
| Change From Baseline in Volume Enhancing at Two Weeks After Completion of Radiation | 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 | 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. |
Countries
United States
Participant flow
Recruitment details
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
There was no randomization to the three strata, which were distinct based on diagnosis and the use of enzyme inducing anti-convulsants (EIACD).
Participants by arm
| Arm | Count |
|---|---|
| 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. | 6 |
| 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. | 43 |
| 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. | 7 |
| 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. | 2 |
| 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. | 3 |
| 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. | 5 |
| 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. | 3 |
| Total | 69 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 4 | 2 | 0 | 0 | 1 | 0 |
| Overall Study | Alternative Therapy | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Disease Progression | 5 | 29 | 2 | 2 | 1 | 4 | 2 |
| Overall Study | Withdrawal by Subject | 0 | 7 | 2 | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | 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 1A-100 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 |
|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 43 Participants | 7 Participants | 2 Participants | 2 Participants | 6 Participants | 5 Participants | 3 Participants | 68 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Age, Continuous | 8.02 years STANDARD_DEVIATION 3.87 | 10.07 years STANDARD_DEVIATION 4.71 | 9.17 years STANDARD_DEVIATION 8.56 | 15.91 years STANDARD_DEVIATION 5.61 | 7.25 years STANDARD_DEVIATION 2.92 | 11.69 years STANDARD_DEVIATION 5.4 | 12.82 years STANDARD_DEVIATION 2.37 | 9.01 years STANDARD_DEVIATION 4.47 |
| Region of Enrollment United States | 43 participants | 7 participants | 2 participants | 3 participants | 6 participants | 5 participants | 3 participants | 69 participants |
| Sex: Female, Male Female | 29 Participants | 4 Participants | 0 Participants | 0 Participants | 3 Participants | 2 Participants | 2 Participants | 40 Participants |
| Sex: Female, Male Male | 14 Participants | 3 Participants | 2 Participants | 3 Participants | 3 Participants | 3 Participants | 1 Participants | 29 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 6 / 6 | 43 / 43 | 7 / 7 | 2 / 2 | 3 / 3 | 5 / 5 | 3 / 3 |
| serious Total, serious adverse events | 2 / 6 | 15 / 43 | 5 / 7 | 1 / 2 | 1 / 3 | 5 / 5 | 1 / 3 |
Outcome results
Primary
Median Progression-free Survival in Newly Diagnosed Brain Stem Gliomas
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
Time frame: Assessed pre-radiation, every 8 weeks for 13 courses of therapy, and then every 12 weeks
Population: Here, we only report the results for Phase-II trial as this objective was specifically for the Phase-II trial. This cohort includes seven patients who were treated during Phase-I at Dose 250 mg/m\^2 of Gefitinib.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stratum 1A-100 mg/m^2 of Gefitinib + Radiation | Median Progression-free Survival in Newly Diagnosed Brain Stem Gliomas | 7.43 Months |
Primary
Median Survival in Newly Diagnosed Brain Stem Gliomas
Overall survival is defined as the interval from initiation of treatment to death or date of last contact for surviving patients
Time frame: Assessed from the start of therapy until three years after initiation of gefitinib therapy
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stratum 1A-100 mg/m^2 of Gefitinib + Radiation | Median Survival in Newly Diagnosed Brain Stem Gliomas | 12.12 Months |
Primary
Number of Participants in Phase I Stratum 1A With Dose-limiting Toxicities (DLT) Observed During the First 8 Weeks of Gefitinib Therapy
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
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Stratum 1A-100 mg/m^2 of Gefitinib + Radiation | Number of Participants in Phase I Stratum 1A With Dose-limiting Toxicities (DLT) Observed During the First 8 Weeks of Gefitinib Therapy | 2 Participants |
| Stratum 1A-250 mg/m^2 of Gefitinib + Radiation | Number of Participants in Phase I Stratum 1A With Dose-limiting Toxicities (DLT) Observed During the First 8 Weeks of Gefitinib Therapy | 0 Participants |
| Stratum 1A-375 mg/m^2 of Gefitinib + Radiation | Number of Participants in Phase I Stratum 1A With Dose-limiting Toxicities (DLT) Observed During the First 8 Weeks of Gefitinib Therapy | 1 Participants |
Secondary
Change From Baseline in Diffusion Ratio at Two Weeks After 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.
Time frame: Baseline and two weeks post completion of radiation
Population: Out of 43 patients, 29 patients had diffusion scans before the treatment started and at the time of the completion of Radiation therapy. Therefore, this analysis is based on the volumetric data from these 29 patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stratum 1A-100 mg/m^2 of Gefitinib + Radiation | Change From Baseline in Diffusion Ratio at Two Weeks After Completion of Radiation | -0.41 Ratio |
p-value: <0.0001Wilcoxon (Mann-Whitney)
Secondary
Change From Baseline in Perfusion Ratio at Two Weeks After 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.
Time frame: Baseline and two weeks post completion of radiation
Population: Out of 43 patients, 20 patients had perfusion scans before the treatment started and at the time of the completion of Radiation therapy. Therefore, this analysis is based on the volumetric data from these 20 patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stratum 1A-100 mg/m^2 of Gefitinib + Radiation | Change From Baseline in Perfusion Ratio at Two Weeks After Completion of Radiation | 0.72 Ratio |
p-value: 0.18Wilcoxon (Mann-Whitney)
Secondary
Change From Baseline in Volume Enhancing at Two Weeks After 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.
Time frame: Baseline and two weeks post completion of radiation
Population: Out of 43 patients, for only 19 patients, enhacing tumor was greater than zero based on brain MRI scans before the treatment started and at the time of the completion of Radiation therapy. Therefore, this analysis is based on the enhancing volumetric data from these 19 patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stratum 1A-100 mg/m^2 of Gefitinib + Radiation | Change From Baseline in Volume Enhancing at Two Weeks After Completion of Radiation | 0.35 cc |
Comparison: 19 patients had Enhancing tumor at both Baseline and Post-RT time points. Thus, the following test was based on these 19 patients.p-value: 0.0546Wilcoxon (Mann-Whitney)
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
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.
Time frame: Baseline and two weeks post completion of radiation
Population: Out of 43 patients, 35 patients had brain MRI before the treatment started and at the time of the completion of Radiation therapy. Therefore, this analysis is based on the volumetric data from these 35 patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stratum 1A-100 mg/m^2 of Gefitinib + Radiation | 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 | -14.03 cc |
p-value: <0.0001Wilcoxon (Mann-Whitney)
Secondary
Clearance of Gefitinib (Cl)
Time frame: Week 2 of course 1
Population: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stratum 1A-100 mg/m^2 of Gefitinib + Radiation | Clearance of Gefitinib (Cl) | 15.2 L/hr/m2 |
| Stratum 1A-250 mg/m^2 of Gefitinib + Radiation | Clearance of Gefitinib (Cl) | 20.9 L/hr/m2 |
| Stratum 1A-375 mg/m^2 of Gefitinib + Radiation | Clearance of Gefitinib (Cl) | 12.8 L/hr/m2 |
| Dose 375 mg/m^2 of Gefitinib | Clearance of Gefitinib (Cl) | 15.0 L/hr/m2 |
Secondary
Elimination Half Life of Gefitinib (t1/2)
Time frame: Week 2 of course 1
Population: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stratum 1A-100 mg/m^2 of Gefitinib + Radiation | Elimination Half Life of Gefitinib (t1/2) | 15.2 hour |
| Stratum 1A-250 mg/m^2 of Gefitinib + Radiation | Elimination Half Life of Gefitinib (t1/2) | 17.6 hour |
| Stratum 1A-375 mg/m^2 of Gefitinib + Radiation | Elimination Half Life of Gefitinib (t1/2) | 9.9 hour |
| Dose 375 mg/m^2 of Gefitinib | Elimination Half Life of Gefitinib (t1/2) | 10.4 hour |
Secondary
Gefitinib Area Under the Concentration Curve From 0-24 Hours (AUC)
Time frame: Week 2 of course 1
Population: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stratum 1A-100 mg/m^2 of Gefitinib + Radiation | Gefitinib Area Under the Concentration Curve From 0-24 Hours (AUC) | 16.4 mcg/L*hr |
| Stratum 1A-250 mg/m^2 of Gefitinib + Radiation | Gefitinib Area Under the Concentration Curve From 0-24 Hours (AUC) | 11.8 mcg/L*hr |
| Stratum 1A-375 mg/m^2 of Gefitinib + Radiation | Gefitinib Area Under the Concentration Curve From 0-24 Hours (AUC) | 5.3 mcg/L*hr |
| Dose 375 mg/m^2 of Gefitinib | Gefitinib Area Under the Concentration Curve From 0-24 Hours (AUC) | 25.3 mcg/L*hr |
Secondary
Mean Tumor to Gray Matter Ratio Measured at 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.
Time frame: Baseline
Population: Out of 43 patients, only 18 Patients had baseline PET scans. Therefore, this analysis is based on these 18 patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stratum 1A-100 mg/m^2 of Gefitinib + Radiation | Mean Tumor to Gray Matter Ratio Measured at Baseline | 0.55 Ratio |
Secondary
Mean Tumor to White Matter Ratio Measured at 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.
Time frame: Baseline
Population: Out of 43 patients, only 18 Patients had baseline PET scans. Therefore, this analysis is based on these 18 patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stratum 1A-100 mg/m^2 of Gefitinib + Radiation | Mean Tumor to White Matter Ratio Measured at Baseline | 1.16 Ratio |
Secondary
Number of Patients With Epidermal Growth Factor Receptor (EGFR) Amplification
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.
Time frame: Pre-treatment
Population: Epidermal growth factor receptor is only possible with tumor sample, which is only potentially available from supratentorial malignant glioma patients treated on Stratum-1B and Stratum-2. Of 10 Stratum-1B and 3 Stratum-2 patients (n=13), tumor material was available from 11 patients (8 in Stratum-1A and 3 in Stratum-2).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Stratum 1A-100 mg/m^2 of Gefitinib + Radiation | Number of Patients With Epidermal Growth Factor Receptor (EGFR) Amplification | 5 Participants |
Secondary
Peak Serum Concentration of Gefitinib (Cmax)
Time frame: Week 2 of course 1
Population: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stratum 1A-100 mg/m^2 of Gefitinib + Radiation | Peak Serum Concentration of Gefitinib (Cmax) | 1.10 mcg/ml |
| Stratum 1A-250 mg/m^2 of Gefitinib + Radiation | Peak Serum Concentration of Gefitinib (Cmax) | 0.83 mcg/ml |
| Stratum 1A-375 mg/m^2 of Gefitinib + Radiation | Peak Serum Concentration of Gefitinib (Cmax) | 0.44 mcg/ml |
| Dose 375 mg/m^2 of Gefitinib | Peak Serum Concentration of Gefitinib (Cmax) | 1.89 mcg/ml |
Secondary
Time of Maximum Clearance of Gefitinib (Tmax)
Time frame: Week 2 of course 1
Population: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stratum 1A-100 mg/m^2 of Gefitinib + Radiation | Time of Maximum Clearance of Gefitinib (Tmax) | 3.2 Hour |
| Stratum 1A-250 mg/m^2 of Gefitinib + Radiation | Time of Maximum Clearance of Gefitinib (Tmax) | 4.2 Hour |
| Stratum 1A-375 mg/m^2 of Gefitinib + Radiation | Time of Maximum Clearance of Gefitinib (Tmax) | 4.9 Hour |
| Dose 375 mg/m^2 of Gefitinib | Time of Maximum Clearance of Gefitinib (Tmax) | 4.2 Hour |