Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Published Results
Related Publications
Trial Contact Information
Registry Information

Alternate Title

Combination Chemotherapy in Treating Patients With Newly Diagnosed Metastatic Ewing's Sarcoma or Primitive Neuroectodermal Tumor

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase II	Treatment	Completed	30 and under	NCI	POG-9457 CCG-P9457, NCT00002643, P9457

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.

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

Expected Enrollment

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.

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.

Bernstein ML, Devidas M, Lafreniere D, et al.: Intensive therapy with growth factor support for patients with Ewing tumor metastatic at diagnosis: Pediatric Oncology Group/Children's Cancer Group Phase II Study 9457--a report from the Children's Oncology Group. J Clin Oncol 24 (1): 152-9, 2006.[PUBMED Abstract]

Souid AK, Newton GL, Dubowy RL, et al.: Determination of the cytoprotective agent WR-2721 (Amifostine, Ethyol) and its metabolites in human blood using monobromobimane fluorescent labeling and high-performance liquid chromatography. Cancer Chemother Pharmacol 42 (5): 400-6, 1998.[PUBMED Abstract]

Souid AK, Fahey RC, Dubowy RL, et al.: WR-2721 (amifostine) infusion in patients with Ewing's sarcoma receiving ifosfamide and cyclophosphamide with mesna: drug and thiol levels in plasma and blood cells, a Pediatric Oncology Group study. Cancer Chemother Pharmacol 44 (6): 498-504, 1999.[PUBMED Abstract]

Trial Contact Information

Trial Lead Organizations

Pediatric Oncology Group

Mark Bernstein, MD, FRCPC, Protocol chair(Contact information may not be current)		Ph: 514-934-4400, ext.2392

Children's Cancer Group

Paul Meyers, MD, Protocol chair		Ph: 212-639-5952; 800-525-2225 Email: meyersp@mskcc.org

Registry Information
Official Title		INTENSIVE THERAPY WITH GROWTH FACTOR SUPPORT FOR PATIENTS WITH EWING'S TUMOR METASTATIC AT DIAGNOSIS: A PEDIATRIC ONCOLOGY GROUP PHASE II STUDY
Trial Start Date		1995-04-01
Registered in ClinicalTrials.gov		NCT00002643
Date Submitted to PDQ		1995-04-01
Information Last Verified		2007-03-23
NCI Grant/Contract Number		U10-CA30969

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