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Gefitinib and Radiation Therapy in Treating Children With Newly Diagnosed Gliomas

15 maj 2014 uppdaterad av: National Cancer Institute (NCI)

Phase I/II Trial of Gefitinib 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

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.

Studieöversikt

Status

Avslutad

Betingelser

Intervention / Behandling

Detaljerad beskrivning

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.

Studietyp

Interventionell

Inskrivning (Faktisk)

69

Fas

  • Fas 2
  • Fas 1

Kontakter och platser

Det här avsnittet innehåller kontaktuppgifter för dem som genomför studien och information om var denna studie genomförs.

Studieorter

  • Förenta staterna
    • Tennessee
      • Memphis, Tennessee, Förenta staterna, 38105
        • Pediatric Brain Tumor Consortium

Deltagandekriterier

Forskare letar efter personer som passar en viss beskrivning, så kallade behörighetskriterier. Några exempel på dessa kriterier är en persons allmänna hälsotillstånd eller tidigare behandlingar.

Urvalskriterier

Åldrar som är berättigade till studier

3 år till 21 år (Barn, Vuxen)

Tar emot friska volontärer

Nej

Kön som är behöriga för studier

Allt

Beskrivning

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

Studieplan

Det här avsnittet ger detaljer om studieplanen, inklusive hur studien är utformad och vad studien mäter.

Hur är studien utformad?

Designdetaljer

  • Primärt syfte: Behandling
  • Tilldelning: N/A
  • Interventionsmodell: Enskild gruppuppgift
  • Maskning: Ingen (Open Label)

Vapen och interventioner

Deltagargrupp / Arm
Intervention / Behandling
Experimentell: Treatment (gefitinib and radiation therapy)

Phase I portion: 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.

Phase II portion: Once the MTD or the recommended Phase-II dose is determined, additional patients who have newly diagnosed BSG are treated at the MTD or the recommended Phase-II dose.
Övrig: laboratoriebiomarköranalys
Korrelativa studier
Läkemedel: gefitinib
Ges oralt
Andra namn:
  • Iressa
Övrig: farmakologisk studie
Korrelativa studier
Andra namn:
  • farmakologiska studier
Strålning: radiation therapy
Undergo standard brain irradiation
Andra namn:
  • bestrålning
  • strålbehandling
  • terapi, strålning

Vad mäter studien?

Primära resultatmått

Resultatmått
Åtgärdsbeskrivning
Tidsram
Number of Participants in Phase I Stratum 1A With Dose-limiting Toxicities (DLT) Observed During the First 8 Weeks of Gefitinib Therapy
Tidsram: 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.
Day 1 of gefitinib therapy to end of week 8
Median Progression-free Survival in Newly Diagnosed Brain Stem Gliomas
Tidsram: 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
Assessed pre-radiation, every 8 weeks for 13 courses of therapy, and then every 12 weeks
Median Survival in Newly Diagnosed Brain Stem Gliomas
Tidsram: 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
Assessed from the start of therapy until three years after initiation of gefitinib therapy

Sekundära resultatmått

Resultatmått
Åtgärdsbeskrivning
Tidsram
Genomsnittligt förhållande mellan tumör och grå substans mätt vid baslinjen
Tidsram: Baslinje
Denna studie försöker karakterisera neuroavbildningsparametrar från positronemissionstomografi. För varje patient identifierades den axiella bilden genom tumören innehållande den maximala aktiviteten per pixel som motsvarar det högsta FluoroDeoxyGlucose (FDG)-upptaget och en region av intresse (ROI) ritades baserat på FDG-definitionen av tumören. De genomsnittliga pixelvärdena inom tumörens ROI normaliserades med de för normal grå substans för att ge förhållanden mellan tumör/grå substans. Varje patient har ett medelvärde för förhållandet mellan tumör och grå substans och medianen för dessa värden över patienterna rapporteras.
Baslinje
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
Tidsram: 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.
Baseline and two weeks post completion of radiation
Change From Baseline in Volume Enhancing at Two Weeks After Completion of Radiation
Tidsram: 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.
Baseline and two weeks post completion of radiation
Change From Baseline in Diffusion Ratio at Two Weeks After Completion of Radiation
Tidsram: 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.
Baseline and two weeks post completion of radiation
Change From Baseline in Perfusion Ratio at Two Weeks After Completion of Radiation
Tidsram: 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.
Baseline and two weeks post completion of radiation
Mean Tumor to White Matter Ratio Measured at Baseline
Tidsram: 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.
Baseline
Peak Serum Concentration of Gefitinib (Cmax)
Tidsram: Week 2 of course 1
Week 2 of course 1
Elimination Half Life of Gefitinib (t1/2)
Tidsram: Week 2 of course 1
Week 2 of course 1
Clearance of Gefitinib (Cl)
Tidsram: Week 2 of course 1
Week 2 of course 1
Time of Maximum Clearance of Gefitinib (Tmax)
Tidsram: Week 2 of course 1
Week 2 of course 1
Gefitinib Area Under the Concentration Curve From 0-24 Hours (AUC)
Tidsram: Week 2 of course 1
Week 2 of course 1
Number of Patients With Epidermal Growth Factor Receptor (EGFR) Amplification
Tidsram: 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.
Pre-treatment

Samarbetspartners och utredare

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Sponsor

National Cancer Institute (NCI)

Utredare

  • Huvudutredare: Jeffrey Geyer, Pediatric Brain Tumor Consortium

Studieavstämningsdatum

Dessa datum spårar framstegen för inlämningar av studieposter och sammanfattande resultat till ClinicalTrials.gov. Studieposter och rapporterade resultat granskas av National Library of Medicine (NLM) för att säkerställa att de uppfyller specifika kvalitetskontrollstandarder innan de publiceras på den offentliga webbplatsen.

Studera stora datum

Studiestart

1 juli 2002

Primärt slutförande (Faktisk)

1 februari 2010

Avslutad studie (Faktisk)

1 mars 2010

Studieregistreringsdatum

Först inskickad

5 augusti 2002

Först inskickad som uppfyllde QC-kriterierna

26 januari 2003

Första postat (Uppskatta)

27 januari 2003

Uppdateringar av studier

Senaste uppdatering publicerad (Uppskatta)

28 maj 2014

Senaste inskickade uppdateringen som uppfyllde QC-kriterierna

15 maj 2014

Senast verifierad

1 december 2012

Mer information

Termer relaterade till denna studie

Ytterligare relevanta MeSH-villkor

Andra studie-ID-nummer

  • NCI-2012-03022 (Registeridentifierare: CTRP (Clinical Trial Reporting Program))
  • U01CA081457 (U.S.S. NIH-anslag/kontrakt)
  • PBTC-007 (Annan identifierare: CTEP)

Läkemedels- och apparatinformation, studiedokument

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