Chemotherapy Plus Peripheral Stem Cell Transplantation in Treating Infants With Malignant Brain or Spinal Cord Tumors

A Pilot Study of Intensive Chemotherapy With Peripheral Stem Cell Support for Infants With Malignant Brain Tumors

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining chemotherapy with peripheral stem cell transplantation may allow the doctors to give higher doses of chemotherapy drugs and kill more tumor cells.

PURPOSE: Phase I trial to study the effectiveness of combination chemotherapy plus peripheral stem cell transplantation in treating infants with malignant brain or spinal cord tumors.

Study Overview

• Status: Completed
• Conditions: Sarcoma; Neuroblastoma; Brain Tumors; Central Nervous System Tumors
• Intervention / Treatment: Drug: cyclophosphamide; Procedure: conventional surgery; Procedure: peripheral blood stem cell transplantation; Drug: etoposide; Drug: vincristine sulfate; Drug: cisplatin; Drug: carboplatin; Drug: thiotepa; Biological: filgrastim

Detailed Description

OBJECTIVES:

• Determine the maximum tolerated dose of thiotepa in infants with malignant brain or spinal cord tumors receiving intensive chemotherapy.
• Determine the feasibility and toxicity of intensive chemotherapy with peripheral blood stem cell (PBSC) rescue in these patients.
• Assess the feasibility of harvesting PBSCs in these patients.
• Determine the complete response rate and overall event-free survival rate in patients treated with this regimen.

OUTLINE: This is a pilot, multicenter study.

Patients undergo surgery for diagnosis and maximal tumor resection.

Within 6 weeks of surgery or when stable, patients begin induction chemotherapy comprising cisplatin IV over 6 hours on day 0; vincristine IV on days 0, 7, and 14; cyclophosphamide IV over 1 hour on days 1-2; and etoposide IV over 1 hour on days 0-2. Twenty four hours after the last cyclophosphamide dose, patients receive filgrastim (G-CSF) subcutaneously (SC) and undergo peripheral blood stem cell harvest 2 days later. Treatment repeats every 21 days for up to 3 courses in the absence of disease progression or unacceptable toxicity.

Within 6 weeks after induction chemotherapy, patients receive consolidation chemotherapy comprising carboplatin IV over 2 hours on days 0-1 followed immediately by escalating doses of thiotepa IV over 2 hours. Patients then undergo peripheral blood stem cell transplantation 48 hours after the last thiotepa dose. Patients receive G-CSF SC daily on days 3 to 21. Treatment repeats every 21 days for up to 3 courses in the absence of disease progression or unacceptable toxicity.

Patients experiencing dose-limiting toxicity due to thiotepa are removed from the study.

Patients are followed at 4 weeks, every 3 months for 1 year, every 6 months for 3 years, and then annually for 3 years or until relapse.

PROJECTED ACCRUAL: A total of 83 patients will be accrued for this study within 1 year.

• Study Type: Interventional
• Enrollment (Actual): 94
• Phase: Phase 1

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
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3E 0V9
      • CancerCare Manitoba
  • Ontario
    • Toronto, Ontario, Canada, M5G 1X8
      • Hospital For Sick Children
  • Saskatchewan
    • Regina, Saskatchewan, Canada, S4T 7T1
      • Allan Blair Cancer Centre at Pasqua Hospital
• United States
  • California
    • Duarte, California, United States, 91010-3000
      • City of Hope Comprehensive Cancer Center
    • Los Angeles, California, United States, 90095-1781
      • Jonsson Comprehensive Cancer Center at UCLA
    • Los Angeles, California, United States, 90027
      • Childrens Hospital Los Angeles
    • Los Angeles, California, United States, 90048-1865
      • Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai Medical Center
    • Madera, California, United States, 93638-8762
      • Children's Hospital Central California
    • Oakland, California, United States, 94609
      • Children's Hospital and Research Center Oakland
    • Orange, California, United States, 92868
      • Children's Hospital of Orange County
    • Sacramento, California, United States, 95825
      • Kaiser Permanente Medical Center - Oakland
    • San Francisco, California, United States, 94115
      • UCSF Helen Diller Family Comprehensive Cancer Center
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Center for Cancer and Blood Disorders
    • Denver, Colorado, United States, 80218
      • Presbyterian - St. Luke's Medical Center
  • Connecticut
    • Farmington, Connecticut, United States, 06360-2875
      • Carole and Ray Neag Comprehensive Cancer Center at the University of Connecticut Health Center
  • Delaware
    • Wilmington, Delaware, United States, 19803
      • Alfred I. DuPont Hospital for Children
  • District of Columbia
    • Washington, District of Columbia, United States, 20010-2970
      • Children's National Medical Center
    • Washington, District of Columbia, United States, 20007
      • Lombardi Comprehensive Cancer Center at Georgetown University Medical Center
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Egleston Campus
    • Augusta, Georgia, United States, 30912-3730
      • MBCCOP - Medical College of Georgia Cancer Center
    • Savannah, Georgia, United States, 31403-3089
      • Curtis and Elizabeth Anderson Cancer Institute at Memorial Health University Medical Center
  • Illinois
    • Chicago, Illinois, United States, 60637-1470
      • University of Chicago Cancer Research Center
  • Indiana
    • Indianapolis, Indiana, United States, 46202-5289
      • Indiana University Melvin and Bren Simon Cancer Center
  • Iowa
    • Iowa City, Iowa, United States, 52242-1002
      • Holden Comprehensive Cancer Center at University of Iowa
  • Kentucky
    • Lexington, Kentucky, United States, 40536-0093
      • Lucille P. Markey Cancer Center at University of Kentucky
    • Louisville, Kentucky, United States, 40232
      • Kosair Children's Hospital
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-0286
      • C.S. Mott Children's Hospital at University of Michigan Medical Center
    • Grand Rapids, Michigan, United States, 49503-2560
      • Butterworth Hospital at Spectrum Health
    • Kalamazoo, Michigan, United States, 49007-5381
      • CCOP - Kalamazoo
  • Minnesota
    • Minneapolis, Minnesota, United States, 55404
      • Children's Hospitals and Clinics of Minnesota - Minneapolis
    • Minneapolis, Minnesota, United States, 55455
      • Masonic Cancer Center at University of Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic Cancer Center
    • St. Paul, Minnesota, United States, 55102-2392
      • Children's Hospitals and Clinics of Minnesota - St. Paul
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Children's Mercy Hospital
  • Nevada
    • Las Vegas, Nevada, United States, 89109-2306
      • CCOP - Nevada Cancer Research Foundation
  • New Jersey
    • Morristown, New Jersey, United States, 07962
      • Overlook Hospital
    • Morristown, New Jersey, United States, 07962
      • Carol G. Simon Cancer Center at Morristown Memorial Hospital
    • Paterson, New Jersey, United States, 07503
      • St. Joseph's Hospital and Medical Center
  • New York
    • Bronx, New York, United States, 10461
      • Albert Einstein Cancer Center at Albert Einstein College of Medicine
    • Mineola, New York, United States, 11501
      • Winthrop University Hospital
    • New York, New York, United States, 10065
      • Memorial Sloan-Kettering Cancer Center
    • 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 Medical Center
    • New York, New York, United States, 10003-3803
      • Beth Israel Medical Center - Petrie Division
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599-7295
      • Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill
  • North Dakota
    • Fargo, North Dakota, United States, 58122
      • CCOP - MeritCare Hospital
  • Ohio
    • Akron, Ohio, United States, 44308-1062
      • Akron Children's Hospital
    • Cincinnati, Ohio, United States, 45229-3039
      • Cincinnati Children's Hospital Medical Center
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Taussig Cancer Center
    • Cleveland, Ohio, United States, 44106-5000
      • Rainbow Babies and Children's Hospital
    • Columbus, Ohio, United States, 43205-2696
      • Nationwide Children's Hospital
    • Dayton, Ohio, United States, 45404-1815
      • Dayton Children's - Dayton
    • Toledo, Ohio, United States, 43614
      • Medical University of Ohio Cancer Center
  • Oregon
    • Portland, Oregon, United States, 97239-3098
      • Knight Cancer Institute At Oregon Health and Science University
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033-0850
      • Penn State Children's Hospital
    • Philadelphia, Pennsylvania, United States, 19104-9786
      • Children's Hospital of Philadelphia
    • Pittsburgh, Pennsylvania, United States, 15213
      • Children's Hospital of Pittsburgh of UPMC
  • South Dakota
    • Sioux Falls, South Dakota, United States, 57105
      • Avera Cancer Institute
    • Sioux Falls, South Dakota, United States, 57117-5039
      • Sanford Cancer Center at Sanford USD Medical Center
  • Texas
    • Amarillo, Texas, United States, 79106
      • Texas Tech University Health Sciences Center School of Medicine - Amarillo
    • Fort Worth, Texas, United States, 76104
      • Cook Children's Medical Center - Fort Worth
    • Lubbock, Texas, United States, 79410
      • Covenant Children's Hospital
    • San Antonio, Texas, United States, 78229-3993
      • Methodist Children's Hospital of South Texas
  • Utah
    • Salt Lake City, Utah, United States, 84113-1100
      • Primary Children's Medical Center
  • Virginia
    • Norfolk, Virginia, United States, 23507-1971
      • Children's Hospital of The King's Daughters
  • Washington
    • Seattle, Washington, United States, 98105
      • Children's Hospital and Regional Medical Center - Seattle
    • Seattle, Washington, United States, 98112
      • Group Health Central Hospital
    • Spokane, Washington, United States, 99210-0248
      • Deaconess Medical Center
    • Tacoma, Washington, United States, 98405
      • Mary Bridge Children's Hospital and Health Center - Tacoma

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 2 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Histologically proven malignant brain or spinal cord tumor, including the following:

  • Primitive neuroectodermal tumor
  • Ganglioneuroblastoma
  • Medulloblastoma neuroblastoma
  • Desmoplastic medulloblastoma
  • Medulloepithelioma
  • Ependymoma neuroepithelioma
  • Anaplastic ependymoma germ cell tumor
  • Astrocytoma germinoma
  • Anaplastic astrocytoma
  • Embryonal carcinoma
  • Glioblastoma endodermal sinus tumor
  • Gliosarcoma malignant teratoma
  • Choroid plexus carcinoma
  • Mixed germ cell tumor
  • Cerebellar sarcoma
  • Pineoblastoma
  • Atypical teratoid/rhabdoid tumor
  • Choriocarcinoma
  • Teratoma (malignant or with malignant transformations)
• Diffusely involved brain stem tumors allowed if there is evidence of brain stem glioma by CT scan or MRI

PATIENT CHARACTERISTICS:

Age:

• 6 months to less than 3 years

Performance Status:

• Not specified

Life Expectancy:

• More than 8 weeks

Hematopoietic:

• Absolute neutrophil count greater than 1,000/mm^3
• Platelet count greater than 100,000/mm^3

Hepatic:

• Bilirubin less than 2.0 mg/dL

Renal:

• Glomerular filtration rate or creatinine clearance greater than 70 mL/min

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• No prior biologic therapy

Chemotherapy:

• No prior chemotherapy

Endocrine therapy:

• Prior corticosteroids allowed

Radiotherapy:

• No prior radiotherapy

Surgery:

• No more than 6 weeks since prior surgery
• Recovered from prior surgery (stable)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (combination chemotherapy, PBSC transplant); Pts undergo conventional surgery for diagnosis & max tumor resection. In 6 wks of surgery or when stable pts begin induction chemotherapy(cisplatin IV over 6 hrs on day 0; vincristine sulfate IV on days 0,7,14; cyclophosphamide IV over 1 hr on days 1-2; and etoposide IV over 1 hr on days 0-2. 24 hrs after the last cyclophosphamide dose, pts receive filgrastim (G-CSF) & undergo peripheral blood stem cell harvest 2 days later. Treatment repeats every 21 days for up to 3 crs. Within 6 wks after induction, pts receive consolidation (carboplatin IV over 2 hrs on days 0-1 next esc. doses of thiotepa IV over 2 hrs. Pts undergo peripheral blood stem cell transplantation 48 hrs after last thiotepa dose. Pts receive G-CSF SC daily on days 3-21. Treatment repeats every 21 days for up to 3 crs. Pts with dose-limiting toxicity due to thiotepa are removed from study. Pts are followed at 4 wks, 3 mths for 1 yr, 6 mths for 3 yrs, annually for 3 yrs or until relapse.

Drug: cyclophosphamide; Given IV; Other Names: Cytoxan; CTX; NSC #026271; Procedure: conventional surgery; Procedure: peripheral blood stem cell transplantation; Drug: etoposide; Given IV; Other Names: VP-16; Etopophos; VePesid; NSC #141540; Drug: vincristine sulfate; Given IV; Other Names: VCR; Oncovin; NSC #067574; Drug: cisplatin; Given IV; Other Names: Platinol-AQ; Cis-diamminedichloroplatinum II; NSC #119875; Drug: carboplatin; Given IV; Other Names: CBDCA; Paraplatin; NSC #241240; Drug: thiotepa; Given IV; Other Names: Tespa; Tspa; NSC #639; Biological: filgrastim; Given IV; Other Names: G-CSF; r-metHuG-CSF; GRANULOCYTE COLONY-STIMULATING FACTOR

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Feasibility	Demonstrate the feasibility of administering this regimen, to select an acceptable Thiotepa dose for Consolidation therapy, and to document significant toxicities and estimate their overall rates	Up to 4 weeks after completion of study treatment
Maximal tolerated dose of thiotepa for consolidation therapy	The dose level will be assigned within 3 working days prior to beginning Consolidation.	9 weeks
Overall rates of significant toxicities including grade IV ototoxicity, electrolytic wasting (grade IV), and hemorrhagic cystitis (grade IV)	Estimates will be obtained using life-table methods with an event defined as the first occurrence of toxicity. Graded using the CCG Toxicity and Complications Criteria.	Up to 6 years

Secondary Outcome Measures

Outcome Measure	Time Frame
Event Free Survival	From the time of study entry to the first occurrence of death by any cause, progression or recurrence of disease or occurrence of a second malignant neoplasm, assessed up

Collaborators and Investigators

• Sponsor: Children's Oncology Group
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Bruce H. Cohen, MD, The Cleveland Clinic

Study record dates

Study Major Dates

• Study Start: March 1, 1998
• Primary Completion (Actual): December 1, 2007
• Study Completion (Actual): October 1, 2011

Study Registration Dates

• First Submitted: November 1, 1999
• First Submitted That Met QC Criteria: November 5, 2003
• First Posted (Estimate): November 6, 2003

Study Record Updates

• Last Update Posted (Estimate): March 28, 2014
• Last Update Submitted That Met QC Criteria: March 27, 2014
• Last Verified: March 1, 2014

More Information

Terms related to this study

• Keywords: untreated childhood brain stem glioma; childhood high-grade cerebral astrocytoma; disseminated neuroblastoma; localized unresectable neuroblastoma; stage 4S neuroblastoma; regional neuroblastoma; untreated childhood medulloblastoma; untreated childhood cerebellar astrocytoma; childhood infratentorial ependymoma; newly diagnosed childhood ependymoma; childhood atypical teratoid/rhabdoid tumor; childhood supratentorial ependymoma; childhood choroid plexus tumor; embryonal childhood rhabdomyosarcoma; previously untreated childhood rhabdomyosarcoma; localized resectable neuroblastoma; childhood low-grade cerebral astrocytoma; untreated childhood supratentorial primitive neuroectodermal tumor; childhood central nervous system choriocarcinoma; childhood central nervous system embryonal tumor; childhood central nervous system germinoma; childhood central nervous system mixed germ cell tumor; childhood central nervous system teratoma; childhood central nervous system yolk sac tumor; childhood spinal cord neoplasm
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms by Histologic Type; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroectodermal Tumors, Primitive; Neuroectodermal Tumors, Primitive, Peripheral; Neoplasms; Brain Neoplasms; Nervous System Neoplasms; Central Nervous System Neoplasms; Neuroblastoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Adjuvants, Immunologic; Cyclophosphamide; Carboplatin; Etoposide; Cisplatin; Lenograstim; Vincristine; Thiotepa
• Other Study ID Numbers: 99703; COG-99703 (Other Identifier: Children's Oncology Group); CCG-99703 (Other Identifier: Children's Cancer Group); CDR0000065924 (Other Identifier: Clinical Trials.gov)