Clinical trial NCT00042991: Gefitinib and Radiation Therapy in Treating Children With Newly Diagnosed Gliomas
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
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
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2003-01-27
Enrollment: 69
Sex: ALL
Minimum age (years): 3
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Number of Participants in Phase I Stratum 1A With Dose-limiting Toxicities (DLT) Observed During the First 8 Weeks of Gefitinib Therapy
timeFrame: Day 1 of gefitinib therapy to end of week 8
measure: Median Progression-free Survival in Newly Diagnosed Brain Stem Gliomas
timeFrame: Assessed pre-radiation, every 8 weeks for 13 courses of therapy, and then every 12 weeks
measure: Median Survival in Newly Diagnosed Brain Stem Gliomas
timeFrame: Assessed from the start of therapy until three years after initiation of gefitinib therapy
Secondary outcomes:
measure: 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
timeFrame: Baseline and two weeks post completion of radiation
measure: Change From Baseline in Volume Enhancing at Two Weeks After Completion of Radiation
timeFrame: Baseline and two weeks post completion of radiation
measure: Change From Baseline in Diffusion Ratio at Two Weeks After Completion of Radiation
timeFrame: Baseline and two weeks post completion of radiation
measure: Change From Baseline in Perfusion Ratio at Two Weeks After Completion of Radiation
timeFrame: Baseline and two weeks post completion of radiation
measure: Mean Tumor to Gray Matter Ratio Measured at Baseline
timeFrame: Baseline
measure: Mean Tumor to White Matter Ratio Measured at Baseline
timeFrame: Baseline
measure: Peak Serum Concentration of Gefitinib (Cmax)
timeFrame: Week 2 of course 1
measure: Elimination Half Life of Gefitinib (t1/2)
timeFrame: Week 2 of course 1
measure: Clearance of Gefitinib (Cl)
timeFrame: Week 2 of course 1
measure: Time of Maximum Clearance of Gefitinib (Tmax)
timeFrame: Week 2 of course 1
measure: Gefitinib Area Under the Concentration Curve From 0-24 Hours (AUC)
timeFrame: Week 2 of course 1
measure: Number of Patients With Epidermal Growth Factor Receptor (EGFR) Amplification
timeFrame: Pre-treatment
Other outcomes:
Locations:
city: Memphis
country: United States
facility: Pediatric Brain Tumor Consortium
state: Tennessee
Study officials:
affiliation: Pediatric Brain Tumor Consortium
name: Jeffrey Geyer
role: PRINCIPAL_INVESTIGATOR
References: