Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Registry Information

Alternate Title

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

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase III	Treatment	Completed	Under 21 at diagnosis	NCI	COG-ACNS0231 ACNS0231, NCT00078988

Objectives

1. 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.
2. Compare the number of hospital days and time to engraftment in patients treated with these regimens.
3. Compare the toxic death rate in patients treated with these regimens.
4. Compare the tolerability of isotretinoin in patients treated with these regimens.

Entry Criteria

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

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

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/mm³
• Platelet count ≥ 100,000/mm³ (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

Expected Enrollment

A total of 80-150 patients (40-75 per treatment arm) will be accrued for this study within 5 years.

Outcomes

Event-free survival
Toxic death

Overall survival

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.

Trial Contact Information

Trial Lead Organizations

Children's Oncology Group

Ziad Khatib, MD, Protocol chair		Ph: 305-666-6511; 800-432-6837 Email: ziad.khatib@mch.com
Sharon Gardner, MD, Protocol co-chair		Ph: 212-263-8520 Email: sharon.gardner@med.nyu.edu

Registry Information
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
Trial Start Date		2004-10-19
Registered in ClinicalTrials.gov		NCT00078988
Date Submitted to PDQ		2004-01-14
Information Last Verified		2006-04-06
NCI Grant/Contract Number		CA98543

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