RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug may kill more tumor cells.

PURPOSE: Phase II trial to study the effectiveness of combination chemotherapy in treating patients with newly diagnosed metastatic Ewing's sarcoma or primitive neuroectodermal tumor.

Condition	Treatment or Intervention	Phase
metastatic tumors of the Ewing's family Neutropenia	Drug: amifostine  Drug: cyclophosphamide  Drug: doxorubicin  Drug: etoposide  Drug: filgrastim  Drug: ifosfamide  Drug: topotecan  Drug: vincristine	Phase II

Further Study Details: 

OBJECTIVES: I. Evaluate the response rate and duration of response of patients with newly diagnosed, metastatic Ewing's sarcoma or primitive neuroectodermal tumor treated with maximally intensified VAdrC (vincristine, doxorubicin, cyclophosphamide) alternating with IE (ifosfamide, etoposide).

II. Evaluate the response to new agents (first topotecan, then topotecan with cyclophosphamide) utilized in an upfront treatment window.

III. Assess the role of surgery with regard to local control of primary and metastatic sites and disease course.

IV. Evaluate whether individual variability in ifosfamide and cyclophosphamide metabolism correlates with toxicity and/or response.

V. Evaluate the rise in the absolute neutrophil count following one dose of filgrastim (G-CSF) given immediately prior to a chemotherapy course as an indicator of bone marrow reserve and subsequent myelosuppression.

VI. Determine if amifostine provides significant chemo-radio protection, particularly against the cumulative toxicities of this intensive therapy.

PROTOCOL OUTLINE: This is a partially randomized, multicenter study. Patients are treated on the investigational window first or proceed to induction therapy immediately, if aggressive treatment is necessary.

Investigational window: Patients receive cyclophosphamide IV and topotecan IV over 30 minutes on days 1-5. Filgrastim (G-CSF) is administered subcutaneously (SQ) beginning day 6 until blood cell counts recover. Treatment is repeated at week 3.

Induction therapy: Patients over 12 months old are randomized to receive amifostine or not. Patients receive etoposide IV over 45 minutes and ifosfamide IV over 2 hours on days 1-5. Amifostine IV over 15 minutes is also administered prior to ifosfamide. Patients receive G-CSF SQ (or IV over 2 hours) beginning on day 6. This course of treatment is administered on weeks 6, 12, and 18.

Patients receive the VAdrC chemotherapy regimen on weeks 9 and 15. This regimen consists of vincristine IV and amifostine IV over 15 minutes on days 1, 8, and 15, cyclophosphamide IV over 30 minutes and doxorubicin IV over 48 hours on days 1 and 2, and G-CSF beginning on day 3.

The VAdrC regimen is continued during local therapy on weeks 21-29 and 39-47, except the day 15 dose of vincristine is omitted, cyclophosphamide is administered on day 1 only on weeks 21, 24, 27, 39, 42, and 45, and doxorubicin is replaced with etoposide IV over 60 minutes on days 1-3 on weeks 24, 28, 42, and 45.

Local therapy begins after 21 weeks of chemotherapy. Patients who respond to chemotherapy and have resectable disease undergo a complete resection with negative margins. Patients with unresectable disease or bulky lesions undergo radiotherapy. Some patients may undergo both surgery and radiotherapy. Local therapy of metastases is delayed until after week 39.

Patients are followed every 3 months for 1 year, every 6 months for 2 years, then annually thereafter.

PROJECTED ACCRUAL: A total of 130 patients will be accrued to the randomized amifostine amendment over 3 years. A total of 30 patients will be accrued on the investigational window.

Ages Eligible for Study:  up to  30 Years

Criteria

PROTOCOL ENTRY CRITERIA:

--Disease Characteristics--

• Newly diagnosed, pathologically confirmed Ewing's sarcoma or primitive neuroectodermal tumor (PNET); Diagnosis established from biopsy of primary tumor; Light microscopy (hematoxylin and eosin stained) consistent with Ewing's sarcoma or PNET; No immunohistochemical or ultrastructural characteristics inconsistent with; Ewing's sarcoma or PNET or suggestive of rhabdomyosarcoma
• Metastatic disease required; Biopsy of radiographically questionable metastases (e.g., pulmonary lesions) required; Chest wall tumor with separate pleural mass considered metastatic; No positive pleural fluid cytology alone

--Prior/Concurrent Therapy--

• No prior chemotherapy or radiotherapy; Resection at diagnosis is discouraged but does not exclude

--Patient Characteristics--

• Age: 30 and under
• Performance status: Not specified
• Hematopoietic: (in the absence of marrow involvement); Absolute neutrophil count greater than 1,200/mm3; Platelet count greater than 120,000/mm3
• Hepatic: Bilirubin less than 1.5 mg/dL; AST/ALT less than 3 times normal
• Renal: Creatinine normal for age; Significant renal abnormality/disease eligible only if: Nuclear GFR is normal; Study coordinator approves
• Cardiovascular: Echocardiogram or MUGA normal

California
      Children's Hospital Los Angeles, Los Angeles,  California,  90027-0700,  United States
      Children's Hospital of Orange County, Orange,  California,  92668,  United States
      David Grant Medical Center, Travis Air Force Base,  California,  94535,  United States
      Jonsson Comprehensive Cancer Center, UCLA, Los Angeles,  California,  90095-1781,  United States
      Long Beach Memorial Medical Center, Long Beach,  California,  90806,  United States
      UCSF Cancer Center and Cancer Research Institute, San Francisco,  California,  94115-0128,  United States
Colorado
      Children's Hospital of Denver, Denver,  Colorado,  80218,  United States
District of Columbia
      Children's National Medical Center, Washington,  District of Columbia,  20010-2970,  United States
Illinois
      University of Chicago Cancer Research Center, Chicago,  Illinois,  60637,  United States
Indiana
      Indiana University Cancer Center, Indianapolis,  Indiana,  46202-5265,  United States
Iowa
      University of Iowa Hospitals and Clinics, Iowa City,  Iowa,  52242,  United States
Kansas
      Via Christi Regional Medical Center-Saint Francis Campus, Wichita,  Kansas,  67214,  United States
Louisiana
      MBCCOP - LSU Medical Center, New Orleans,  Louisiana,  70112,  United States
Michigan
      CCOP - Kalamazoo, Kalamazoo,  Michigan,  49007-3731,  United States
      University of Michigan Comprehensive Cancer Center, Ann Arbor,  Michigan,  48109-0752,  United States
Minnesota
      Mayo Clinic Cancer Center, Rochester,  Minnesota,  55905,  United States
      University of Minnesota Cancer Center, Minneapolis,  Minnesota,  55455,  United States
Missouri
      Children's Mercy Hospital - Kansas City, Kansas City,  Missouri,  64108,  United States
Nebraska
      University of Nebraska Medical Center, Omaha,  Nebraska,  68198-3330,  United States
New Jersey
      Cancer Institute of New Jersey, New Brunswick,  New Jersey,  08901,  United States
New York
      Herbert Irving Comprehensive Cancer Center, New York,  New York,  10032,  United States
      Kaplan Cancer Center, New York,  New York,  10016,  United States
      Memorial Sloan-Kettering Cancer Center, New York,  New York,  10021,  United States
North Carolina
      Lineberger Comprehensive Cancer Center, UNC, Chapel Hill,  North Carolina,  27599-7295,  United States
      Memorial Mission Hospital, Asheville,  North Carolina,  28801,  United States
North Dakota
      CCOP - Merit Care Hospital, Fargo,  North Dakota,  58122,  United States
      Veterans Affairs Medical Center - Fargo, Fargo,  North Dakota,  58102,  United States
Ohio
      Children's Hospital Medical Center - Cincinnati, Cincinnati,  Ohio,  45229-3039,  United States
      Children's Hospital of Columbus, Columbus,  Ohio,  43205-2696,  United States
      Ireland Cancer Center, Cleveland,  Ohio,  44106-5065,  United States
Oregon
      Doernbecher Children's Hospital, Portland,  Oregon,  97201-3098,  United States
Pennsylvania
      Children's Hospital of Philadelphia, Philadelphia,  Pennsylvania,  19104,  United States
      Children's Hospital of Pittsburgh, Pittsburgh,  Pennsylvania,  15213,  United States
Tennessee
      Vanderbilt Cancer Center, Nashville,  Tennessee,  37232-6838,  United States
Texas
      Medical City Dallas Hospital, Dallas,  Texas,  75230,  United States
      San Antonio Military Pediatric Cancer and Blood Disorders Center, Lackland Air Force Base,  Texas,  78236-5300,  United States
      University of Texas - MD Anderson Cancer Center, Houston,  Texas,  77030,  United States
      University of Texas Health Science Center at San Antonio, San Antonio,  Texas,  78284,  United States
Utah
      Huntsman Cancer Institute, Salt Lake City,  Utah,  84132,  United States
Virginia
      Cancer Center, University of Virginia HSC, Charlottesville,  Virginia,  22908,  United States
Washington
      Children's Hospital and Regional Medical Center - Seattle, Seattle,  Washington,  98105,  United States
      Fred Hutchinson Cancer Research Center, Seattle,  Washington,  98109,  United States
Wisconsin
      University of Wisconsin Comprehensive Cancer Center, Madison,  Wisconsin,  53792,  United States
Australia, Western Australia
      Princess Margaret Hospital for Children, Perth,  Western Australia,  6001,  Australia
Canada, British Columbia
      British Columbia Children's Hospital, Vancouver,  British Columbia,  V6H 3V4,  Canada
Canada, Nova Scotia
      IWK Grace Health Centre, Halifax,  Nova Scotia,  B3J 3G9,  Canada
Canada, Quebec
      Montreal Children's Hospital, Montreal,  Quebec,  H3H 1P3,  Canada
Puerto Rico
      University of Puerto Rico School of Medicine Medical Sciences Campus, San Juan,  00936-5067,  Puerto Rico
Switzerland
      Clinique de Pediatrie, Geneva,  1211,  Switzerland

Study chairs or principal investigators

Mark Lawrence Bernstein,  Study Chair,  Pediatric Oncology Group   
Paul A. Meyers,  Study Chair

Study ID Numbers:  CDR0000064137; POG-9457
Record last reviewed:  July 2004
Last Updated:  October 13, 2004
Record first received:  November 1, 1999
ClinicalTrials.gov Identifier:  NCT00002643
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08