Erlotinib and Radiation Therapy in Treating Young Patients With Newly Diagnosed Glioma

Study Overview
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Brief Summary
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RATIONALE: Radiation therapy uses high-energy x-rays to kill tumor cells. Erlotinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. It may also make tumor cells more sensitive to radiation therapy. Giving radiation therapy together with erlotinib may kill more tumor cells. PURPOSE: This phase I/II trial is studying the side effects and best dose of erlotinib when given together with radiation therapy and to see how well they work in treating young patients with newly diagnosed glioma.

Detailed Description
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OBJECTIVES: Primary Determine the maximum tolerated dose and dose-limiting toxicity of erlotinib when administered during and after radiotherapy in young patients with newly diagnosed high-grade glioma and unfavorable low-grade glioma. Determine the 1- and 2-year progression-free survival of patients treated with this regimen. Secondary Determine the toxic effects of this regimen in these patients. Correlate genetic abnormalities in epidermal growth factor receptor (EGFR) and components of downstream pathways with treatment response in patients treated with this regimen. Determine the ability of erlotinib to inhibit EGFR signaling in patients with high-grade glioma who require second surgery. Determine the pharmacokinetics of erlotinib and its metabolites in these patients. Correlate plasma and cerebrospinal fluid levels of vascular endothelial growth factor and basic fibroblast growth factor with tumor response in patients treated with this regimen. Correlate irradiation dosimetry with patterns of failure, standard and investigational imaging, and toxicity in patients treated with this regimen. OUTLINE: This is a phase I dose-escalation study of erlotinib followed by a phase II study. Phase I: Patients undergo radiotherapy once daily, 5 days week, for approximately 6½ weeks. Beginning on the first day of radiotherapy, patients receive oral erlotinib once daily for up to 2 years. Cohorts of patients receive escalating doses of erlotinib until the maximum tolerated dose (MTD) is determined. Phase II: Patients will receive erlotinib as in phase I at the MTD and undergo radiotherapy as in phase I. PROJECTED ACCRUAL: A total of 75-80 patients (15-20 for the phase I portion and 60 for the phase II portion) will be accrued for this study.

Official Title
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A Phase I/II Trial of a New Tyrosine Kinase Inhibitor (Tarceva; Erlotinib Hydrochloride; OSI-774) During and After Radiotherapy in the Treatment of Patients With Newly Diagnosed High Grade Glioma and Unfavorable Low-Grade Glioma

Conditions
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Brain and Central Nervous System Tumors

Intervention / Treatment
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* Drug: Erlotinib hydrochloride


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Diagnosis of high-grade glioma of 1 of the following types: Unfavorable low-grade glioma Gliomatosis cerebri or bithalamic involvement Histologically confirmed high-grade glioma (WHO grade III or IV) of 1 of the following subtypes: Anaplastic astrocytoma Anaplastic oligodendroglioma Anaplastic oligoastrocytoma Anaplastic ganglioglioma Pleomorphic xanthoastrocytoma with anaplastic features Malignant glioneuronal tumor Glioblastoma multiforme Gliosarcoma Newly diagnosed disease Intracranial or spinal cord tumors allowed PATIENT CHARACTERISTICS: Age 3 to 21 Performance status Karnofsky 40-100% (age 17 to 21 years) OR Lansky 40-100% (age 3 to 16 years) Life expectancy Not specified Hematopoietic Absolute neutrophil count ≥ 1,000/mm^3 Platelet count ≥ 100,000/mm^3 (transfusion independent) Hemoglobin ≥ 8 g/dL (transfusion allowed) Hepatic Bilirubin < 1.5 times upper limit of normal (ULN) SGPT < 5 times ULN Albumin ≥ 2 g/dL Renal Creatinine < 2 times normal OR Glomerular filtration rate > 70 mL/min Cardiovascular No significant cardiovascular problem Pulmonary No significant pulmonary problem Other Not pregnant or nursing Fertile patients must use effective contraception No uncontrolled infection No significant medical illness PRIOR CONCURRENT THERAPY: Biologic therapy No prior or concurrent biologic agents Chemotherapy No prior or concurrent chemotherapy Endocrine therapy Not specified Radiotherapy No prior radiotherapy Surgery No more than 42 days since prior surgery Other No other prior or concurrent anticancer or experimental treatment

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Patients with High-Grade/Low-Grade Glioma<br>Patients with newly diagnosed high-grade glioma (excluding those originating in the brain stem) and unfavorable low-grade glioma who are ≥ 3 years and <26 years of age. Patients receiving enzyme-inducing anticonvulsants (EIACs) are not eligible for this study. Patients with spinal cord tumors will be eligible for the Phase I and Phase II component of this study, but they will not be taken into consideration to estimate PFS in the Phase II component of this trial because of their notoriously worse prognosis. Patients receive erlotinib hydrochloride. | Drug: Erlotinib hydrochloride<br>* This study has 2 components: a Phase I component which estimated the MTD and DLT(s) of erlotinib given once a day during and after conventionally fractionated RT for a period of 8 weeks (DLT-evaluation period), followed by continuous administration of this medication for up to 3 years; and a Phase II component where erlotinib will be given at the MTD during and after RT for 2 years. The recommended dose of erlotinib for the Phase II component of the current study is 120mg/m2 per day (maximum dose of 200mg per day).<br>* Other names: NSC#718781;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose-limiting Toxicity (DLT) | DLT was defined as any of the following toxicities attributable to erlotinib therapy: thrombocytopenia grade 3 and 4; neutropenia grade 4; or any grade 3 and 4 non-hematologic toxicity except for grade 3 diarrhea and grade 3 nausea and vomiting lasting ≤48 hours in participants not receiving optimal supportive therapy, grade 3 skin rash, which did not affect normal daily activities, grade 3 fever or nonneutropenic infection, grade 3 seizures, grade 3 weight gain or loss, and grade 3 transaminase elevation that returned to grade 1 or baseline within 7 days. After enrollment of the first 4 participants, grade 3 and 4 electrolyte abnormalities that resolved to ≤grade 2 within 7 days were excluded as DLT. Toxicities were graded according to the Common Terminology Criteria for Adverse Events version 3.0. | During the first 8 weeks of therapy | 
| Maximum Tolerated Dose (MTD) of Erlotinib | MTD was defined as the highest dosage level in which no more than one of six assessable participants experienced dose-limiting toxicities (DLT). The dosage of erlotinib was increased by approximately 30% in each dosage level starting at 80% of the MTD in adults with solid tumors. A traditional 3+3 dose escalation scheme was used to estimate the MTD. | During the first 8 weeks of therapy. | 
| Progression Free Survival (PFS) | Progression-free survival (PFS) distributions for the Phase II participants with anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM) were calculated using Kaplan-Meier estimates (n=41). PFS was defined as the interval between treatment start and initial failure, including clinical or radiologic progression or death from any cause. PFS was not calculated for the other disease types. | 1 and 2 years after end of therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax of Erlotinib and Its Metabolite OSI-420 | Although the calculated dose of erlotinib was rounded to the nearest 25 mg, the actual dosage administered to patients was within 12% of the prescribed dosage in all but 1 patient. The latter patient received erlotinib at the lowest dosage level and the actual dosage was 19% higher than the calculated dose. | After first dose of therapy, and Day 8 of therapy | 
| Erlotinib Tmax | Although the calculated dose of erlotinib was rounded to the nearest 25 mg, the actual dosage administered to patients was within 12% of the prescribed dosage in all but 1 patient. The latter patient received erlotinib at the lowest dosage level and the actual dosage was 19% higher than the calculated dose. | After first dose of therapy | 
| AUC Time 0-infinite (AUCinf) of Erlotinib and Its Metabolite OSI-420 | Although the calculated dose of erlotinib was rounded to the nearest 25 mg, the actual dosage administered to patients was within 12% of the prescribed dosage in all but 1 patient. The latter patient received erlotinib at the lowest dosage level and the actual dosage was 19% higher than the calculated dose. | After first dose of therapy, and Day 8 of therapy | 
| Number of Positive Mutations of EGFR and Downstream Pathways | Statistical analyses of genomic changes, expression profiles and validation studies should be considered in an exploratory and hypothesis-generating context. Fresh frozen tumor tissue was obtained at the time of tumor resection and diagnosis. DNA was extracted from formalin-fixed, paraffin-embedded tissue. The entire PTEN coding sequence (exons 1-9), exons 1, 9 and 20 of PIK3CA, and exons 17-24 of EGFR were evaluated using exon-specific PCR amplification, and immunohistochemistry was done. Tumor lesions were considered positive if >25% cells were immunoreactive. | Once at tumor resection and diagnosis | 
| Ability of Erlotinib to Inhibit EGFR Signaling | The objective was to test the ability of erlotinib to inhibit the EGFR signaling in patients with high-grade glioma who required a second surgery. This outcome was not assessed due to insufficient availability of tumor and control samples for analysis. | 5 Years | 
| Correlation Between Standard Magnetic Resonance Imaging and Investigational Radiologic Techniques in Assessing Tumor Response to This Treatment | This objective was to prospectively investigate the correlation between standard magnetic resonance imaging (MRI) and investigational radiologic techniques (MR spectroscopy, perfusion/diffusion, PET scan, DEMRI/BLAST) in assessing tumor response to this treatment. | at diagnosis and regular intervals during therapy (up to 2 years after start of therapy) | 
| To Prospectively Investigate the Technical Factors Involved in Planning and Administering Conformal Fractionated RT as Outlined in This Study, and to Correlate RT Dosimetry With Patterns of Failure, Standard and Investigational Imaging and Toxicity |  | 5 Years | 
| Plasma and CSF Levels of VEGF, bFGF, and SDF1 | This objective was to determine the plasma and CSF levels of the VEGF, bFGF, and SDF1 at diagnosis, and the plasma levels of these factors at regular intervals during therapy, and to analyze the association of these results with tumor response. | at diagnosis and regular intervals during therapy (up to 2 years after start of therapy) | 
| Number of Participants Experiencing Grade 3 or 4 Toxicity Events | Adverse events were collected systematically for each of the 44 Phase II participants from the time of enrollment to the completion of therapy (approximately 2 years from start of therapy). | From start of therapy through 2 years. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adult anaplastic astrocytoma, adult anaplastic oligodendroglioma, adult glioblastoma, adult giant cell glioblastoma, adult gliosarcoma, adult mixed glioma, childhood mixed glioma, untreated childhood cerebellar astrocytoma, childhood high-grade cerebral astrocytoma, childhood low-grade cerebral astrocytoma, childhood oligodendroglioma, childhood spinal cord neoplasm