Radiation Therapy, Temozolomide, and Lomustine in Treating Young Patients With Newly Diagnosed Gliomas

Study Overview
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Brief Summary
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This phase II trial is studying how well giving radiation therapy together with temozolomide and lomustine works in treating young patients with newly diagnosed gliomas. Radiation therapy uses high energy x-rays to kill tumor cells. Drugs used in chemotherapy, such as temozolomide and lomustine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving radiation therapy together with temozolomide and lomustine after surgery may kill any remaining tumor cells.

Detailed Description
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PRIMARY OBJECTIVES: I. Compare event-free survival of pediatric patients with newly diagnosed high-grade gliomas treated with adjuvant radiotherapy and temozolomide followed by temozolomide and lomustine with historical controls. II. Determine the toxicity of this regimen in these patients. III. Correlate MGMT and p53 expression in tumor tissue with outcome in patients treated with this regimen. IV. Correlate polymorphisms in GSTP1, GSTM1 and GSTT1 genes and GSTP1 protein expression in tumors with survival in patients treated with this regimen. OUTLINE: This is a pilot, multicenter study. CHEMORADIOTHERAPY: Patients receive oral temozolomide once daily on days 1-42. Patients also undergo concurrent radiotherapy once daily on days 1-5, 8-12, 15-19, 22-26, 29-33 and 36-40. Patients who did not undergo prior gross total resection also undergo boost radiotherapy once daily on days 43-47. MAINTENANCE CHEMOTHERAPY: Four weeks after completion of chemoradiotherapy, patients receive oral temozolomide once daily on days 1-5 and oral lomustine on day 1. Treatment repeats every 42 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients are followed every 3 months for 1 year, every 6 months for 3 years and then annually thereafter.

Official Title
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A Phase II Study of Concurrent Radiation and Temozolomide Followed By Temozolomide and CCNU in the Treatment of Children With High-Grade Glioma

Conditions
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Anaplastic Astrocytoma, Central Nervous System Neoplasm, Glioblastoma, Gliosarcoma, Spinal Cord Neoplasm

Intervention / Treatment
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* Other: Laboratory Biomarker Analysis
* Drug: Lomustine
* Radiation: Radiation Therapy
* Drug: Temozolomide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed, newly diagnosed high-grade glioma of 1 of the following histologies: Anaplastic astrocytoma Glioblastoma multiforme Gliosarcoma Primary spinal cord malignant gliomas allowed No primary brainstem tumors Has undergone surgical resection or biopsy of the tumor within the past 31 days Pre-operative and post-operative brain MRI with and without gadolinium-contrast OR pre-operative and post-operative spine MRI for spinal cord primaries Post-operative MRI not required for patients who undergo biopsy only No evidence of neuraxis dissemination Spine MRI and cerebrospinal fluid cytology required only if clinically indicated Performance status - Karnofsky 50-100% (for patients > 16 years of age) Performance status - Lansky 50-100% (for patients ≤ 16 years of age) At least 8 weeks Absolute neutrophil count ≥ 1,000/mm^3 Platelet count ≥ 100,000/mm^3 (transfusion independent) Hemoglobin ≥ 8 g/dL (transfusions allowed) Bilirubin ≤ 1.5 times upper limit of normal (ULN) ALT ≤ 2.5 times ULN Albumin ≥ 2 g/dL Creatinine ≤ 1.5 times ULN Creatinine clearance or radioisotope glomerular filtration rate ≥ lower limit of normal No evidence of dyspnea at rest No exercise intolerance Pulse oximetry ≥ 94% (if determination is clinically indicated) Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for 2 months after study participation Able to swallow oral medication Seizures allowed provided they are well controlled with anticonvulsants No hypersensitivity to temozolomide No prior biologic agents No prior chemotherapy Prior corticosteroids allowed No concurrent corticosteroids as an antiemetic Concurrent corticosteroids allowed only for treatment of increased intracranial pressure No concurrent radiotherapy using cobalt-60 See Disease Characteristics No other prior treatment No concurrent phenobarbital or cimetidine No concurrent co-trimoxazole for Pneumocystis carinii pneumonia prophylaxis during study chemoradiotherapy

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: Treatment (lomustine, temozolomide, radiation therapy)<br>Patients receive oral temozolomide once daily on days 1-42. Patients also undergo concurrent radiotherapy once daily on days 1-5, 8-12, 15-19, 22-26, 29-33 and 36-40. Patients who did not undergo prior gross total resection also undergo boost radiotherapy once daily on days 43-47. Four weeks after completion of chemoradiotherapy, patients receive oral temozolomide once daily on days 1-5 and oral lomustine on day 1. Treatment repeats every 42 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Lomustine<br>* Given PO<br>* Other names: WR-139017;Radiation: Radiation Therapy<br>* Undergo radiation therapy<br>* Other names: Therapy, Radiation;Drug: Temozolomide<br>* Given PO<br>* Other names: TMZ;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| One Year Overall Survival | Estimated one year survival using the Kaplan-Meier methodology. | One year | 
| Occurrence of Death Attributable to Complications of Protocol Therapy | Number of deaths due to complications of protocol therapy. | While receiving protocol therapy (up to 301 days excluding delays) or within 30 days of Termination of Protocol Therapy |