Topotecan, G-CSF, and Radiation Therapy in Treating Young Patients With Newly Diagnosed Brain Stem Glioma

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as topotecan, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Colony-stimulating factors, such as G-CSF, may increase the number of immune cells found in bone marrow or peripheral blood and may help the immune system recover from the side effects of chemotherapy. Radiation therapy uses high-energy x-rays to kill tumor cells. Topotecan may make tumor cells more sensitive to radiation therapy . Giving topotecan and G-CSF together with radiation therapy may be an effective treatment for brain stem glioma. PURPOSE: This phase I/II trial is studying the side effects and best dose of topotecan when given together with G-CSF and radiation therapy and to see how well they work in treating young patients with newly diagnosed brain stem glioma.

Detailed Description
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OBJECTIVES: Primary Determine the feasibility of escalating the dose of topotecan when administered with filgrastim (G-CSF) and radiotherapy, in terms of increasing the topotecan dose 25-50% above the maximum tolerated dose (MTD) determined in a prior phase I study, in young patients with newly diagnosed malignant intrinsic pontine brain stem glioma. (Phase I) Determine the dose-limiting toxic effects of topotecan in these patients. (Phase I) Determine the 1-year event-free survival and overall survival of patients treated with this regimen (at the MTD of topotecan determined in phase I). (Phase II) Determine the toxicity of this regimen in these patients. (Phase II) Secondary Determine the pharmacokinetics of this regimen in these patients. OUTLINE: This is a multicenter, phase I, dose-escalation study of topotecan followed by a phase II study. Phase I: Patients receive topotecan IV over 30 minutes followed by radiotherapy once daily, 5 days a week for 6-7 weeks. During chemoradiotherapy, patients also receive filgrastim (G-CSF) IV or subcutaneously daily, if needed, until blood counts recover. Treatment continues in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of topotecan until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 out of 6 patients experience dose-limiting toxicity. Phase II: Patients receive topotecan (at the MTD determined in phase I ), G-CSF, and radiotherapy as in phase I. After completion of study treatment, patients are followed within 2 weeks, every 3 months for 1.5 years, every 6 months for 1.5 years, and then annually until disease relapse. PROJECTED ACCRUAL: A total of 3-72 patients (3-12 for phase I and 60 for phase II) will be accrued for this study within approximately 3 years.

Official Title
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A Phase I/II Study of Topotecan With G-CSF and Radiation Therapy in Children With Malignant Intrinsic Pontine Brainstem Gliomas of Childhood

Conditions
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Brain Tumors, Central Nervous System Tumors

Intervention / Treatment
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* Biological: filgrastim
* Drug: topotecan hydrochloride
* Radiation: radiation therapy


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Diagnosis of intrinsic pontine brain stem glioma within the past 30 days Histologic confirmation not required provided the tumor has a pontine epicenter AND exhibits diffuse (rather than focal) involvement of ≥ 2/3 of the pons with or without extension to the adjacent medulla or midbrain* NOTE: *Brain stem tumors that do not meet these criteria must be histologically confirmed as grade III or IV malignant glioma Measurable disease by radiographic imaging Post-operative MRI required within the past 30 days if patient had a biopsy or surgical resection No disseminated disease No neurofibromatosis type 1 PATIENT CHARACTERISTICS: Age 3 to 21 at diagnosis Performance status Lansky 50-100% OR Karnofsky 50-100% Life expectancy At least 8 weeks Hematopoietic Absolute neutrophil count ≥ 1,000/mm^3 Platelet count ≥ 100,000/mm^3 (transfusion independent) Hemoglobin ≥ 10.0 g/dL (transfusion allowed) Hepatic Bilirubin ≤ 1.5 times upper limit of normal (ULN) ALT < 2.5 times ULN Renal Creatinine clearance or radioisotope glomerular filtration rate ≥ 70 mL/min OR Creatinine based on age as follows: No greater than 0.8 mg/dL (for patients ≤ 5 years of age) No greater than 1.0 mg/dL (for patients 6 to 10 years of age) No greater than 1.2 mg/dL (for patients 11 to 15 years of age) No greater than 1.5 mg/dL (for patients over 15 years of age) Other Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception Not severely somnolent or comatose Central cortical neurotoxicity scale < grade 3 PRIOR CONCURRENT THERAPY: Biologic therapy No concurrent immunomodulating agents Chemotherapy No other concurrent anticancer chemotherapy Endocrine therapy Concurrent corticosteroids allowed for neurological deficits related to the tumor Radiotherapy No prior radiotherapy Surgery See Disease Characteristics Prior biopsy or surgical resection for malignant brain stem glioma allowed Other No other prior therapy for malignant brain stem glioma

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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Level I (0.5 mg/m^2)<br>Radiation Therapy + Topotecan hydrochloride daily before each dose of irradiation (radiation therapy) + filgrastim (G-CSF) (p.r.n) | Biological: filgrastim<br>* Given PO<br>* Other names: NSC #614629;Drug: topotecan hydrochloride<br>* Given IV<br>* Other names: NSC #609699;Radiation: radiation therapy<br> <br> * Other names: used.;|
| Experimental: Dose Level 2 (0.6 mg/m^2)<br>Radiation Therapy + Topotecan hydrochloride daily before each dose of irradiation (radiation therapy) + filgrastim (G-CSF) (p.r.n.) | Biological: filgrastim<br>* Given PO<br>* Other names: NSC #614629;Drug: topotecan hydrochloride<br>* Given IV<br>* Other names: NSC #609699;Radiation: radiation therapy<br> <br> * Other names: used.;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to treatment failure (e.g., tumor progression, tumor recurrence, or death from any cause) |  | From date of enrollment until the first occurrence of relapse, progressive disease, secondary malignancy, or death or until last contact if none of these events occur, assessed up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to death |  | From the time of study entry to the first occurrence of death by any cause | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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untreated childhood brain stem glioma