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

Brain Tumor Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00078988
• Other study ID #: ACNS0231
• Secondary ID: COG-ACNS0231CDR0
• Status: Completed
• Phase: Phase 3
• First received: March 8, 2004
• Last updated: May 6, 2015
• Start date: October 2004
• Est. completion date: September 2006

Study information

• Verified date: May 2015
• Source: Children's Oncology Group
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1
• Est. completion date: September 2006
• Est. primary completion date: September 2006
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A to 20 Years

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Brain Tumor
• Central Nervous System Neoplasms
• Central Nervous System Tumor
• Nervous System Neoplasms

Intervention

Biological:
• filgrastim
Given IV

Drug:
• carboplatin
Given IV
• etoposide
Given IV
• isotretinoin
Given IV
• thiotepa
Given IV

Procedure:
• autologous bone marrow transplantation
Peripheral blood stem cells or bone marrow will be reinfused about 72 hours following completion of the last dose of chemotherapy (Day 0)
• peripheral blood stem cell transplantation
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.

Locations

Country	Name	City	State
Australia	Princess Margaret Hospital for Children	Perth	Western Australia
Canada	McMaster Children's Hospital at Hamilton Health Sciences	Hamilton	Ontario
Canada	Hopital Sainte Justine	Montreal	Quebec
Canada	Montreal Children's Hospital at McGill University Health Center	Montreal	Quebec
Canada	Centre Hospitalier Universitaire de Quebec	Ste-Foy	Quebec
Canada	Hospital for Sick Children	Toronto	Ontario
Canada	Children's & Women's Hospital of British Columbia	Vancouver	British Columbia
United States	Children's Hospital Medical Center of Akron	Akron	Ohio
United States	Emory University Hospital - Atlanta	Atlanta	Georgia
United States	CancerCare of Maine at Eastern Maine Medial Center	Bangor	Maine
United States	Floating Hospital for Children at Tufts - New England Medical Center	Boston	Massachusetts
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	Hollings Cancer Center at Medical University of South Carolina	Charleston	South Carolina
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Rainbow Babies and Children's Hospital	Cleveland	Ohio
United States	Columbus Children's Hospital	Columbus	Ohio
United States	Children's Medical Center - Dayton	Dayton	Ohio
United States	Children's Hospital Cancer Center	Denver	Colorado
United States	Barbara Ann Karmanos Cancer Institute	Detroit	Michigan
United States	INOVA Fairfax Hospital	Fairfax	Virginia
United States	Cook Children's Medical Center - Fort Worth	Fort Worth	Texas
United States	University of Florida Shands Cancer Center	Gainesville	Florida
United States	Spectrum Health Cancer Care - Butterworth Campus	Grand Rapids	Michigan
United States	Van Elslander Cancer Center at St. John Hospital and Medical Center	Grosse Pointe Woods	Michigan
United States	Penn State Cancer Institute at Milton S. Hershey Medical Center	Hershey	Pennsylvania
United States	Cancer Research Center of Hawaii	Honolulu	Hawaii
United States	Indiana University Cancer Center	Indianapolis	Indiana
United States	St. Vincent Indianapolis Hospital	Indianapolis	Indiana
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	Nemours Children's Clinic	Jacksonville	Florida
United States	Children's Mercy Hospital	Kansas City	Missouri
United States	Arkansas Cancer Research Center at University of Arkansas for Medical Sciences	Little Rock	Arkansas
United States	Kosair Children's Hospital	Louisville	Kentucky
United States	Covenant Children's Hospital	Lubbock	Texas
United States	University of Wisconsin Comprehensive Cancer Center	Madison	Wisconsin
United States	Marshfield Clinic - Marshfield Center	Marshfield	Wisconsin
United States	Miami Children's Hospital	Miami	Florida
United States	University of Miami Sylvester Comprehensive Cancer Center	Miami	Florida
United States	Children's Hospital of Minnesota - Minneapolis	Minneapolis	Minnesota
United States	Fairview University Medical Center - University Campus	Minneapolis	Minnesota
United States	Cancer Institute of New Jersey at UMDNJ - Robert Wood Johnson Medical School	New Brunswick	New Jersey
United States	Herbert Irving Comprehensive Cancer Center at Columbia University	New York	New York
United States	NYU Cancer Institute at New York University Medical Center	New York	New York
United States	Children's Hospital of the King's Daughters	Norfolk	Virginia
United States	Children's Hospital and Research Center - Oakland	Oakland	California
United States	Oklahoma University Medical Center	Oklahoma City	Oklahoma
United States	Massey Cancer Center at Virginia Commonwealth University	Richmond	Virginia
United States	James P. Wilmot Cancer Center at University of Rochester Medical Center	Rochester	New York
United States	University of California Davis Cancer Center	Sacramento	California
United States	Primary Children's Medical Center	Salt Lake City	Utah
United States	Children's Hospital and Health Center - San Diego	San Diego	California
United States	Sioux Valley Hospital and University of South Dakota Medical Center	Sioux Falls	South Dakota
United States	Siteman Cancer Center at Barnes-Jewish Hospital	St. Louis	Missouri
United States	All Children's Hospital	St. Petersburg	Florida
United States	SUNY Upstate Medical University Hospital	Syracuse	New York
United States	St. Joseph's Cancer Institute at St. Joseph's Hospital	Tampa	Florida
United States	New York Medical College	Valhalla	New York
United States	Children's National Medical Center	Washington	District of Columbia
United States	Kaplan Cancer Center at St. Mary's Medical Center	West Palm Beach	Florida

Sponsors (2)

Lead Sponsor	Collaborator
Children's Oncology Group	National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Australia,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Primary	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	Yes
Secondary	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	No