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

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 Overview

• Status: Completed
• Conditions: Brain Tumor; Central Nervous System Tumor
• Intervention / Treatment: Drug: etoposide; Drug: carboplatin; Drug: thiotepa; Biological: filgrastim; Drug: isotretinoin; Procedure: autologous bone marrow transplantation; Procedure: peripheral blood stem cell transplantation

Detailed 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.

• Study Type: Interventional
• Enrollment (Actual): 1
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Western Australia
    • Perth, Western Australia, Australia, 6001
      • Princess Margaret Hospital for Children
• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V6H 3V4
      • Children's & Women's Hospital of British Columbia
  • Ontario
    • Hamilton, Ontario, Canada, L8N 3Z5
      • McMaster Children's Hospital at Hamilton Health Sciences
    • Toronto, Ontario, Canada, M5G 1X8
      • Hospital for Sick Children
  • Quebec
    • Montreal, Quebec, Canada, H3H 1P3
      • Montreal Children's Hospital at McGill University Health Center
    • Montreal, Quebec, Canada, H3T 1C5
      • Hopital Sainte Justine
    • Ste-Foy, Quebec, Canada, G1V 4G2
      • Centre Hospitalier Universitaire de Quebec
• United States
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • Arkansas Cancer Research Center at University of Arkansas for Medical Sciences
  • California
    • Oakland, California, United States, 94609-1809
      • Children's Hospital and Research Center - Oakland
    • Sacramento, California, United States, 95817
      • University of California Davis Cancer Center
    • San Diego, California, United States, 92123-4282
      • Children's Hospital and Health Center - San Diego
  • Colorado
    • Denver, Colorado, United States, 80218-1088
      • Children's Hospital Cancer Center
  • District of Columbia
    • Washington, District of Columbia, United States, 20010-2970
      • Children's National Medical Center
  • Florida
    • Gainesville, Florida, United States, 32610-0232
      • University of Florida Shands Cancer Center
    • Jacksonville, Florida, United States, 32207
      • Nemours Children's Clinic
    • Miami, Florida, United States, 33136
      • University of Miami Sylvester Comprehensive Cancer Center
    • Miami, Florida, United States, 33155
      • Miami Children's Hospital
    • St. Petersburg, Florida, United States, 33701
      • All Children's Hospital
    • Tampa, Florida, United States, 33607
      • St. Joseph's Cancer Institute at St. Joseph's Hospital
    • West Palm Beach, Florida, United States, 33407
      • Kaplan Cancer Center at St. Mary's Medical Center
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University Hospital - Atlanta
  • Hawaii
    • Honolulu, Hawaii, United States, 95813
      • Cancer Research Center of Hawaii
  • Indiana
    • Indianapolis, Indiana, United States, 46202-5289
      • Indiana University Cancer Center
    • Indianapolis, Indiana, United States, 46260
      • St. Vincent Indianapolis Hospital
  • Kentucky
    • Louisville, Kentucky, United States, 40232
      • Kosair Children's Hospital
  • Maine
    • Bangor, Maine, United States, 04401
      • CancerCare of Maine at Eastern Maine Medial Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02111
      • Floating Hospital for Children at Tufts - New England Medical Center
  • Michigan
    • Detroit, Michigan, United States, 48201-1379
      • Barbara Ann Karmanos Cancer Institute
    • Grand Rapids, Michigan, United States, 49503-2560
      • Spectrum Health Cancer Care - Butterworth Campus
    • Grosse Pointe Woods, Michigan, United States, 48236
      • Van Elslander Cancer Center at St. John Hospital and Medical Center
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • Fairview University Medical Center - University Campus
    • Minneapolis, Minnesota, United States, 55404
      • Children's Hospital of Minnesota - Minneapolis
  • Mississippi
    • Jackson, Mississippi, United States, 39216-4505
      • University of Mississippi Medical Center
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Children's Mercy Hospital
    • St. Louis, Missouri, United States, 63110
      • Siteman Cancer Center at Barnes-Jewish Hospital
  • New Jersey
    • New Brunswick, New Jersey, United States, 08903
      • Cancer Institute of New Jersey at UMDNJ - Robert Wood Johnson Medical School
  • New York
    • Buffalo, New York, United States, 14263-0001
      • Roswell Park Cancer Institute
    • New York, New York, United States, 10016
      • NYU Cancer Institute at New York University Medical Center
    • New York, New York, United States, 10032
      • Herbert Irving Comprehensive Cancer Center at Columbia University
    • Rochester, New York, United States, 14642
      • James P. Wilmot Cancer Center at University of Rochester Medical Center
    • Syracuse, New York, United States, 13210
      • SUNY Upstate Medical University Hospital
    • Valhalla, New York, United States, 10595
      • New York Medical College
  • Ohio
    • Akron, Ohio, United States, 44308-1062
      • Children's Hospital Medical Center of Akron
    • Cincinnati, Ohio, United States, 45229-3039
      • Cincinnati Children's Hospital Medical Center
    • Cleveland, Ohio, United States, 44106-5000
      • Rainbow Babies and Children's Hospital
    • Columbus, Ohio, United States, 43205-2696
      • Columbus Children's Hospital
    • Dayton, Ohio, United States, 45404-1815
      • Children's Medical Center - Dayton
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Oklahoma University Medical Center
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033-0850
      • Penn State Cancer Institute at Milton S. Hershey Medical Center
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Hollings Cancer Center at Medical University of South Carolina
  • South Dakota
    • Sioux Falls, South Dakota, United States, 57117-5039
      • Sioux Valley Hospital and University of South Dakota Medical Center
  • Texas
    • Fort Worth, Texas, United States, 76104-9958
      • Cook Children's Medical Center - Fort Worth
    • Lubbock, Texas, United States, 79410
      • Covenant Children's Hospital
  • Utah
    • Salt Lake City, Utah, United States, 84113-1100
      • Primary Children's Medical Center
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Inova Fairfax Hospital
    • Norfolk, Virginia, United States, 23507-1971
      • Children's Hospital of the King's Daughters
    • Richmond, Virginia, United States, 23298-0037
      • Massey Cancer Center at Virginia Commonwealth University
  • Wisconsin
    • Madison, Wisconsin, United States, 53792-6164
      • University of Wisconsin Comprehensive Cancer Center
    • Marshfield, Wisconsin, United States, 54449
      • Marshfield Clinic - Marshfield Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 20 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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 SC once daily beginning on day 1 and continuing until blood counts recover. Autologous PBSC or bone marrow are reinfused on day 0.	Drug: etoposide; Given IV; Other Names: VP-16; Etopophos; VePesid; NSC #141540; Drug: carboplatin; Given IV; Other Names: CBDCA; NSC #241240; Paraplain; Drug: thiotepa; Given IV; Other Names: Thiophosphamide; Tespa; Triethylenethiophosphoramide Tspa; WR-45312; NSC#6396; Biological: filgrastim; Given IV; Other Names: G-CSF; Granulocyte Colony-Stimulating Factor; r-metHuG-CSF; Neupogen; NSC 614629; Drug: isotretinoin; Given IV; Other Names: Accutane; 13-cis-retinoic acid; RO-43; 780; NSC#329481; 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); Other Names: Stem Cell Reinfusion; Procedure: 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.; Other Names: Peripheral Stem Cell Collection
Experimental: 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.	Drug: carboplatin; Given IV; Other Names: CBDCA; NSC #241240; Paraplain; Drug: thiotepa; Given IV; Other Names: Thiophosphamide; Tespa; Triethylenethiophosphoramide Tspa; WR-45312; NSC#6396; Biological: filgrastim; Given IV; Other Names: G-CSF; Granulocyte Colony-Stimulating Factor; r-metHuG-CSF; Neupogen; NSC 614629; 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); Other Names: Stem Cell Reinfusion; Procedure: 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.; Other Names: Peripheral Stem Cell Collection
Experimental: Arm III (isotretinoin); Patients receive oral isotretinoin twice daily on days 1-14. Treatment repeats every 28 days for a total of 6 courses.	Drug: isotretinoin; Given IV; Other Names: Accutane; 13-cis-retinoic acid; RO-43; 780; NSC#329481
No Intervention: Arm IV (no isotretinoin); Patients do not receive maintenance therapy.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Children's Oncology Group
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Sharon L. Gardner, MD, NYU Langone Health; Study Chair: Ziad Khatib, MD, Nicklaus Children's Hospital f/k/a Miami Children's Hospital

Study record dates

Study Major Dates

• Study Start: October 1, 2004
• Primary Completion (Actual): September 1, 2006
• Study Completion (Actual): September 1, 2006

Study Registration Dates

• First Submitted: March 8, 2004
• First Submitted That Met QC Criteria: March 8, 2004
• First Posted (Estimate): March 9, 2004

Study Record Updates

• Last Update Posted (Estimate): May 7, 2015
• Last Update Submitted That Met QC Criteria: May 6, 2015
• Last Verified: May 1, 2015

More Information

Terms related to this study

• Keywords: childhood high-grade cerebral astrocytoma; recurrent childhood cerebellar astrocytoma; recurrent childhood cerebral astrocytoma
• Additional Relevant MeSH Terms: Nervous System Diseases; Neoplasms; Neoplasms by Site; Nervous System Neoplasms; Central Nervous System Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Dermatologic Agents; Adjuvants, Immunologic; Carboplatin; Etoposide; Lenograstim; Thiotepa; Isotretinoin
• Other Study ID Numbers: ACNS0231; U10CA098543 (U.S. NIH Grant/Contract); COG-ACNS0231 (Other Identifier: Children's Oncology Group); CDR0000353207 (Other Identifier: NCI); NCI-2012-02578 (Registry Identifier: CTRP (Clinical Trial Reporting Program))