Clinical trial NCT00002643: Combination Chemotherapy in Treating Patients With Newly Diagnosed Metastatic Ewing's Sarcoma or Primitive Neuroectodermal Tumor
Official title: INTENSIVE THERAPY WITH GROWTH FACTOR SUPPORT FOR PATIENTS WITH EWING'S TUMOR METASTATIC AT DIAGNOSIS: A PEDIATRIC ONCOLOGY GROUP PHASE II STUDY
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Neutropenia
Sarcoma
Keywords: neutropenia
metastatic Ewing sarcoma/peripheral primitive neuroectodermal tumor
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
Collaborators: name: Children's Cancer Group
First posted: 2003-06-18
Enrollment: 130
Sex: ALL
Maximum age (years): 30
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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

Detailed description: 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.

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.

Eligibility 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

PATIENT CHARACTERISTICS:

* Age: 30 and under
* Absolute neutrophil count greater than 1,200/mm3
* Platelet count greater than 120,000/mm3
* Bilirubin less than 1.5 mg/dL
* AST/ALT less than 3 times normal
* Creatinine normal for age
* Significant renal abnormality/disease eligible only if nuclear GFR is normal and study coordinator approves
* Echocardiogram or MUGA normal

PRIOR CONCURRENT THERAPY:

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

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Long Beach
country: United States
facility: Long Beach Memorial Medical Center
state: California
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles
state: California
city: Los Angeles
country: United States
facility: Jonsson Comprehensive Cancer Center, UCLA
state: California
city: Orange
country: United States
facility: Children's Hospital of Orange County
state: California
city: San Francisco
country: United States
facility: UCSF Cancer Center and Cancer Research Institute
state: California
city: Travis Air Force Base
country: United States
facility: David Grant Medical Center
state: California
city: Denver
country: United States
facility: Children's Hospital of Denver
state: Colorado
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Chicago
country: United States
facility: University of Chicago Cancer Research Center
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University Cancer Center
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa Hospitals and Clinics
state: Iowa
city: Wichita
country: United States
facility: Via Christi Regional Medical Center-Saint Francis Campus
state: Kansas
city: New Orleans
country: United States
facility: MBCCOP - LSU Medical Center
state: Louisiana
city: Ann Arbor
country: United States
facility: University of Michigan Comprehensive Cancer Center
state: Michigan
city: Kalamazoo
country: United States
facility: CCOP - Kalamazoo
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota Cancer Center
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic Cancer Center
state: Minnesota
city: Kansas City
country: United States
facility: Children's Mercy Hospital - Kansas City
state: Missouri
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: New Brunswick
country: United States
facility: Cancer Institute of New Jersey
state: New Jersey
city: New York
country: United States
facility: Kaplan Cancer Center
state: New York
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: New York
country: United States
facility: Herbert Irving Comprehensive Cancer Center
state: New York
city: Asheville
country: United States
facility: Memorial Mission Hospital
state: North Carolina
city: Chapel Hill
country: United States
facility: Lineberger Comprehensive Cancer Center, UNC
state: North Carolina
city: Fargo
country: United States
facility: Veterans Affairs Medical Center - Fargo
state: North Dakota
city: Fargo
country: United States
facility: CCOP - Merit Care Hospital
state: North Dakota
city: Cincinnati
country: United States
facility: Children's Hospital Medical Center - Cincinnati
state: Ohio
city: Cleveland
country: United States
facility: Ireland Cancer Center
state: Ohio
city: Columbus
country: United States
facility: Children's Hospital of Columbus
state: Ohio
city: Portland
country: United States
facility: Doernbecher Children's Hospital
state: Oregon
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt Cancer Center
state: Tennessee
city: Dallas
country: United States
facility: Medical City Dallas Hospital
state: Texas
city: Houston
country: United States
facility: University of Texas - MD Anderson Cancer Center
state: Texas
city: Lackland Air Force Base
country: United States
facility: San Antonio Military Pediatric Cancer and Blood Disorders Center
state: Texas
city: San Antonio
country: United States
facility: University of Texas Health Science Center at San Antonio
state: Texas
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute
state: Utah
city: Charlottesville
country: United States
facility: Cancer Center, University of Virginia HSC
state: Virginia
city: Seattle
country: United States
facility: Children's Hospital and Regional Medical Center - Seattle
state: Washington
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center
state: Washington
city: Madison
country: United States
facility: University of Wisconsin Comprehensive Cancer Center
state: Wisconsin
city: Perth
country: Australia
facility: Princess Margaret Hospital for Children
state: Western Australia
city: Vancouver
country: Canada
facility: British Columbia Children's Hospital
state: British Columbia
city: Halifax
country: Canada
facility: IWK Grace Health Centre
state: Nova Scotia
city: Montreal
country: Canada
facility: Montreal Children's Hospital
state: Quebec
city: San Juan
country: Puerto Rico
facility: University of Puerto Rico School of Medicine Medical Sciences Campus
city: Geneva
country: Switzerland
facility: Clinique de Pediatrie
Study officials:
affiliation: Montreal Children's Hospital at McGill University Health Center
name: Mark L. Bernstein, MD, FRCPC
role: STUDY_CHAIR
affiliation: Memorial Sloan Kettering Cancer Center
name: Paul A. Meyers, MD
role: STUDY_CHAIR
References:
citation: Souid AK, Fahey RC, Dubowy RL, Newton GL, Bernstein ML. 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. 1999;44(6):498-504. doi: 10.1007/s002800051124.
citation: Bernstein ML, Devidas M, Lafreniere D, Souid AK, Meyers PA, Gebhardt M, Stine K, Nicholas R, Perlman EJ, Dubowy R, Wainer IW, Dickman PS, Link MP, Goorin A, Grier HE; Pediatric Oncology Group; Children's Cancer Group Phase II Study 9457; Children's Oncology Group. 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. 2006 Jan 1;24(1):152-9. doi: 10.1200/JCO.2005.02.1717.
citation: Souid AK, Newton GL, Dubowy RL, Fahey RC, Bernstein ML. 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. 1998;42(5):400-6. doi: 10.1007/s002800050836.