High-Dose Chemotherapy Plus Autologous Stem Cell Transplantation Compared With Intermediate-Dose Chemotherapy Plus Autologous Stem Cell Transplantation With or Without Isotretinoin in Treating Young Patients With Recurrent High-Grade Gliomas

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as carboplatin, thiotepa, and etoposide, work in different ways to stop tumor cells from dividing so they stop growing or die. Combining chemotherapy with autologous stem cell transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more tumor cells. Isotretinoin may be effective in preventing recurrence of glioma. It is not yet known which regimen of chemotherapy plus autologous stem cell transplantation with or without isotretinoin is more effective in treating recurrent high-grade glioma. PURPOSE: This randomized phase III trial is studying high-dose chemotherapy or intermediate-dose chemotherapy followed by autologous stem cell transplantation to see how well it works compared to high-dose chemotherapy or intermediate-dose chemotherapy followed by autologous stem cell transplantation and isotretinoin in treating young patients with recurrent high-grade glioma.

Detailed Description
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OBJECTIVES: Compare the event-free survival and overall survival of pediatric patients with recurrent high-grade gliomas treated with a single course of high-dose carboplatin, etoposide, and thiotepa and autologous stem cell transplantation vs multiple courses of intermediate-dose carboplatin and thiotepa and autologous stem cell transplantation with or without isotretinoin. Compare the number of hospital days and time to engraftment in patients treated with these regimens. Compare the toxic death rate in patients treated with these regimens. Compare the tolerability of isotretinoin in patients treated with these regimens. OUTLINE: This is a randomized, multicenter study. Patients are stratified according to pathologic diagnosis (glioblastoma multiforme vs anaplastic astrocytoma vs other high-grade glioma). Chemotherapy and autologous stem cell reinfusion (ASCR): Patients are randomized to 1 of 2 treatment arms. Arm I (high-dose chemotherapy and ASCR): Patients receive high-dose chemotherapy comprising carboplatin IV over 4 hours on days -8 to -6; thiotepa IV over 3 hours and etoposide IV over 3 hours on days -5 to -3; and filgrastim (G-CSF) IV or subcutaneously (SC) once daily beginning on day 1 and continuing until blood counts recover. Autologous peripheral blood stem cells (PBSC) or bone marrow are reinfused on day 0. Arm II (intermediate-dose chemotherapy and ASCR): Patients receive intermediate-dose chemotherapy comprising carboplatin IV over 4 hours and thiotepa IV over 3 hours on days 1-2 and G-CSF IV or SC once daily beginning on day 4 and continuing until blood counts recover. Autologous PBSC or bone marrow are reinfused on day 3. Treatment repeats every 28 days for a total of 3 courses. Maintenance therapy: After recovery from chemotherapy (approximately day 30 post-transplantation), all patients are further randomized to 1 of 2 maintenance arms. Arm I: Patients receive oral isotretinoin twice daily on days 1-14. Treatment repeats every 28 days for a total of 6 courses. Arm II: Patients do not receive maintenance therapy. In all arms, treatment continues in the absence of disease progression. Patients are followed every 3 months for 1 year, every 6 months for 3 years, and then annually thereafter. PROJECTED ACCRUAL: A total of 80-150 patients (40-75 per treatment arm) will be accrued for this study within 5 years.

Official Title
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A Phase III Randomized Trial for the Treatment of Pediatric High Grade Gliomas at First Recurrence With a Single High Dose Chemotherapy and Autologous Stem Cell Transplant Versus Three Courses of Intermediate Dose Chemotherapy With Peripheral Blood Stem Cell (PBSC) Support

Conditions
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Brain Tumor, Central Nervous System Tumor

Intervention / Treatment
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* Biological: filgrastim
* Drug: carboplatin
* Drug: etoposide
* Drug: isotretinoin
* Drug: thiotepa
* Procedure: autologous bone marrow transplantation
* Procedure: peripheral blood stem cell transplantation


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed diagnosis of 1 of the following high-grade gliomas: Glioblastoma multiforme Anaplastic astrocytoma Gliosarcoma Disease in first relapse No primary brainstem or spinal cord gliomas No secondary glioblastomas arising after prior treatment for a non-glial tumor Prior local radiotherapy of 5,000-6,000 cGy required Less than 1.5 cm of residual gadolinium-enhancing tumor in maximal cross-sectional diameter by MRI No metastatic tumor by spinal MRI PATIENT CHARACTERISTICS: Age Under 21 at diagnosis Performance status Lansky 50-100% OR Karnofsky 50-100% Life expectancy Not specified Hematopoietic Absolute neutrophil count ≥ 500/mm^3 Platelet count ≥ 100,000/mm^3 (transfusion independent) Hepatic Bilirubin ≤ 1.5 times upper limit of normal (ULN) AST or ALT < 2.5 times ULN Renal Glomerular filtration rate ≥ 60 mL/min AND/OR Creatinine clearance ≥ 60 mL/min Cardiovascular Shortening fraction ≥ 27% by echocardiogram OR Ejection fraction ≥ 50% by MUGA Pulmonary No dyspnea at rest No exercise intolerance Pulse oximetry > 94% Other Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception PRIOR CONCURRENT THERAPY: Biologic therapy Not specified Chemotherapy More than 4 weeks since prior chemotherapy No prior thiotepa No prior myeloablative chemotherapy Endocrine therapy No concurrent corticosteroids Radiotherapy See Disease Characteristics More than 8 weeks since prior radiotherapy No prior craniospinal radiotherapy Surgery Not specified

Ages Eligible for Study
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Maximum Age: 20 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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (high-dose chemotherapy and ASCR)<br>Patients receive high-dose chemotherapy comprising carboplatin IV over 4 hours on days -8 to -6; thiotepa IV over 3 hours and etoposide IV over 3 hours on days -5 to -3; and filgrastim (G-CSF) IV or SC once daily beginning on day 1 and continuing until blood counts recover. Autologous PBSC or bone marrow are reinfused on day 0. | Biological: filgrastim<br>* Given IV<br>* Other names: NSC 614629;Drug: carboplatin<br>* Given IV<br>* Other names: NSC #241240;Drug: etoposide<br>* Given IV<br>* Other names: NSC #141540;Drug: isotretinoin<br>* Given IV<br>* Other names: NSC#329481;Drug: thiotepa<br>* Given IV<br>* Other names: NSC#6396;Procedure: autologous bone marrow transplantation<br>* Peripheral blood stem cells or bone marrow will be reinfused about 72 hours following completion of the last dose of chemotherapy (Day 0)<br>* Other names: Stem Cell Reinfusion;Procedure: peripheral blood stem cell transplantation<br>* Filgrastim is to be given daily in the afternoon for 4 days prior to the first harvest and continued until the completion of the daily harvests. The daily PBSC harvesting should be started prior to the fifth dose of filgrastim.<br>* Other names: Peripheral Stem Cell Collection;|
| Experimental: Arm II (intermediate-dose chemotherapy and ASCR)<br>Patients receive intermediate-dose chemotherapy comprising carboplatin IV over 4 hours and thiotepa IV over 3 hours on days 1-2 and G-CSF IV or SC once daily beginning on day 4 and continuing until blood counts recover. Autologous PBSC or bone marrow are reinfused on day 3. Treatment repeats every 28 days for a total of 3 courses. | Biological: filgrastim<br>* Given IV<br>* Other names: NSC 614629;Drug: carboplatin<br>* Given IV<br>* Other names: NSC #241240;Drug: thiotepa<br>* Given IV<br>* Other names: NSC#6396;Procedure: autologous bone marrow transplantation<br>* Peripheral blood stem cells or bone marrow will be reinfused about 72 hours following completion of the last dose of chemotherapy (Day 0)<br>* Other names: Stem Cell Reinfusion;Procedure: peripheral blood stem cell transplantation<br>* Filgrastim is to be given daily in the afternoon for 4 days prior to the first harvest and continued until the completion of the daily harvests. The daily PBSC harvesting should be started prior to the fifth dose of filgrastim.<br>* Other names: Peripheral Stem Cell Collection;|
| Experimental: Arm III (isotretinoin)<br>Patients receive oral isotretinoin twice daily on days 1-14. Treatment repeats every 28 days for a total of 6 courses. | Drug: isotretinoin<br>* Given IV<br>* Other names: NSC#329481;|
| No Intervention: Arm IV (no isotretinoin)<br>Patients do not receive maintenance therapy. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free survival | The primary endpoint for the evaluation of treatment efficacy will be event-free survival (EFS) | om study entry to disease progression, disease relapse, occurrence of a second malignant neoplasm, or death from any cause. assessed up to 4 years | 
| Toxic death attributable to complications of treatment in the absence of tumor progression as assessed by NCI Common Toxicity Criteria for Adverse Events (CTCAE) version 3.0 | Toxic death will be monitored separately in each of the two chemotherapy groups | Up to 4 years after completion of study treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | Secondary endpoints include overall survival (OS), which is defined as the time from study entry to death from any cause, assessed up to 4 years | ondary e ndpoints include overall survival (OS), which is defined as the time from study entry to death from any cause assessed up to 4 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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childhood high-grade cerebral astrocytoma, recurrent childhood cerebellar astrocytoma, recurrent childhood cerebral astrocytoma