Erlotinib Alone or in Combination With Radiation Therapy in Treating Young Patients With Refractory or Relapsed Malignant Brain Tumors or Newly Diagnosed Brain Stem Glioma

Study Overview
=================
Brief Summary
-----------------
RATIONALE: Erlotinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving erlotinib together with radiation therapy may kill more tumor cells. PURPOSE: This phase I trial is studying the side effects and best dose of erlotinib when given alone or together with radiation therapy in treating young patients with refractory or relapsed malignant brain tumors or newly diagnosed brain stem glioma.

Detailed Description
-----------------
OBJECTIVES: Primary Establish the maximum tolerated dose of single-agent erlotinib hydrochloride in pediatric patients with refractory or relapsed malignant brain tumors and in combination with radiotherapy in pediatric patients with newly diagnosed brain stem glioma. Secondary Determine dose-limiting toxicities of these regimens. Define the safety profile of these regimens. Characterize the pharmacokinetic behavior of erlotinib hydrochloride in these patients. Evaluate the efficacy of these regimens. Correlate expression and mutations of epidermal growth factor receptor with treatment response. OUTLINE: This is a multicenter, nonrandomized, open-label, dose-escalation study of erlotinib hydrochloride. Patients are assigned to 1 of 2 treatment groups according to disease. Group 1 (refractory or relapsed malignant brain tumors): Patients receive oral erlotinib hydrochloride once daily on days 1-21. Treatment repeats every 21 days in the absence of unacceptable toxicity or disease progression. Cohorts of 3-6 patients receive escalating doses of erlotinib hydrochloride until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity (DLT). Group 2 (newly diagnosed brain stem glioma): Patients receive oral erlotinib hydrochloride once daily on days 1-21. Treatment repeats every 21 days in the absence of unacceptable toxicity or disease progression. Beginning on day 1, patients also undergo radiotherapy 5 days a week for 6 weeks . Cohorts of 1-2 patients receive escalating doses of erlotinib hydrochloride until the MTD is determined. The MTD is defined as the dose resulting in 25% of patients experiencing DLT at 6 weeks. Blood is collected for pharmacokinetic assessments and pharmacogenetic genotyping for analysis of enzyme polymorphisms. Tumor tissue may be assessed for epidermal growth factor receptor mutations. After completion of study treatment, patients are followed every 3 months. PROJECTED ACCRUAL: A total of 48 patients will be accrued for this study.

Official Title
-----------------
Phase I Studies of TARCEVA™ (ERLOTINIB HYDROCHLORIDE, OSI-774) as Single Agent in Children With Refractory and Relapsed Malignant Brain Tumors and in Combination With Irradiation in Newly Diagnosed Brain Stem Glioma

Conditions
-----------------
Brain and Central Nervous System Tumors

Intervention / Treatment
-----------------
* Drug: erlotinib hydrochloride
* Genetic: mutation analysis
* Genetic: polymorphism analysis
* Other: laboratory biomarker analysis
* Other: pharmacological study
* Radiation: radiation therapy


Participation Criteria
=================
Eligibility Criteria
-----------------
DISEASE CHARACTERISTICS: Diagnosis of 1 of the following: Histologically or cytologically confirmed malignant brain tumor Refractory to first-line therapy or relapsed after conventional therapy No effective conventional therapy exists Histologically confirmed brain stem glioma Newly diagnosed disease No pilocytic glioma Measurable or evaluable disease PATIENT CHARACTERISTICS: WHO performance status 0-2 OR Lansky play scale 50-100% Patients with motor paresis due to disease are eligible Neurological deficits must be stable for ≥ 1 week Life expectancy ≥ 8 weeks Absolute neutrophil count > 1,500/mm³ Platelet count ≥ 100,000/mm³ Hemoglobin ≥ 8 g/dL AST/ALT ≤ 2.5 times upper limit of normal (ULN) Bilirubin ≤ 1.5 times ULN Creatinine < 1.5 times ULN OR creatinine clearance ≥ 70 mL/min No other serious, uncontrolled illness No active infection No organ toxicity ≥ grade 2 except alopecia and neurological symptoms due to disease Must be able to take oral medication Patients with newly diagnosed brain stem glioma with difficulty swallowing may be eligible Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No evidence of pulmonary dysfunction or pre-existing lung disease No myocardial infarction within the past year No severe cardiac pathology No significant ophthalmologic abnormality including, but not limited to, any of the following: Severe dry eye syndrome Keratoconjunctivitis sicca Sjögren's syndrome Severe exposure keratitis Any other disorder likely to increase the risk of corneal epithelial lesions PRIOR CONCURRENT THERAPY: More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas) More than 6 weeks since prior radiotherapy No concurrent warfarin No other concurrent anticancer or investigational agents

Ages Eligible for Study
-----------------
Minimum Age: 1 Year
Maximum Age: 21 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: erlotinib hydrochloride|nan|
|Genetic: mutation analysis|nan|
|Genetic: polymorphism analysis|nan|
|Other: laboratory biomarker analysis|nan|
|Other: pharmacological study|nan|
|Radiation: radiation therapy|nan|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose of erlotinib hydrochloride when given alone and in combination with radiotherapy |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-limiting toxicities |  |  | 
| Safety |  |  | 
| Pharmacokinetic behavior of erlotinib hydrocloride |  |  | 
| Efficacy |  |  | 
| Correlation of expression and mutations of epidermal growth factor receptor with treatment response |  |  | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
untreated childhood brain stem glioma, recurrent childhood cerebellar astrocytoma, recurrent childhood cerebral astrocytoma, recurrent childhood ependymoma, recurrent childhood medulloblastoma, recurrent childhood supratentorial primitive neuroectodermal tumor, recurrent childhood visual pathway and hypothalamic glioma, childhood central nervous system germ cell tumor, childhood choroid plexus tumor, childhood craniopharyngioma, childhood grade I meningioma, childhood grade II meningioma, childhood grade III meningioma, childhood low-grade cerebral astrocytoma, childhood infratentorial ependymoma, childhood supratentorial ependymoma, recurrent childhood brain tumor, recurrent childhood subependymal giant cell astrocytoma, recurrent childhood pineoblastoma