Official Title: “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”

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.

Study Type: Interventional

Study Design: Treatment, Randomized, Active Control

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.

Intervention(s) in this Clinical Trial

• Biological: filgrastim
• Drug: carboplatin
• Drug: etoposide
• Drug: isotretinoin
• Drug: thiotepa
• Procedure: autologous bone marrow transplantation
• Procedure: peripheral blood stem cell transplantation

Primary Measures

• Event-free survival
  • Safety Issue?: No
• Toxic death
  • Safety Issue?: Yes

Secondary Measures

• Overall survival
  • Safety Issue?: No

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

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: N/A

Maximum Age for this Clinical Trial: 20 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Children's Oncology Group

Overall Clinical Trial Officials and Contacts

Ziad Khatib, MD Study Chair Miami Children's Hospital  

Information obtained from ClinicalTrials.gov on July 02, 2009

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00078988

Study ID Number: CDR0000353207

ClinicalTrials.gov Identifier: NCT00078988

Health Authority: United States: Federal Government

Clinical trial summary from the National Cancer Institute's PDQ® database