Combination Chemotherapy With or Without Topotecan in Treating Patients With Newly Diagnosed Localized Ewing's Sarcoma - Full Text View

Sponsors and Collaborators:	Children's Oncology Group National Cancer Institute (NCI)
Information provided by:	National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:	NCT00334867

Purpose

RATIONALE: Drugs used in chemotherapy, such as vincristine, doxorubicin, cyclophosphamide, ifosfamide, etoposide, and topotecan, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more tumor cells. Giving chemotherapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving chemotherapy after surgery may kill any tumor cells that remain after surgery. It is not yet known which combination chemotherapy regimen is more effective in treating Ewing's sarcoma.

PURPOSE: This randomized phase III trial is studying combination chemotherapy and topotecan to see how well they work compared with combination chemotherapy alone in treating patients with newly diagnosed localized Ewing's sarcoma.

Condition	Intervention	Phase
Sarcoma	Drug: cyclophosphamide Drug: dexrazoxane hydrochloride Drug: doxorubicin hydrochloride Drug: etoposide Drug: ifosfamide Drug: topotecan hydrochloride Drug: vincristine sulfate Procedure: conventional surgery Procedure: radiation therapy	Phase III

MedlinePlus related topics: Cancer Soft Tissue Sarcoma

Drug Information available for: Doxorubicin Doxorubicin hydrochloride Ifosfamide Cyclophosphamide Etoposide Vincristine sulfate Vincristine Topotecan hydrochloride Topotecan Etoposide phosphate Dexrazoxane Dexrazoxane hydrochloride ICRF 159 Razoxane

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Treatment, Randomized
Official Title:	A Phase III Randomized Trial of Adding Vincristine-Topotecan-Cyclophosphamide to Standard Chemotherapy in Initial Treatment of Non-Metastatic Ewing Sarcoma

Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:

Event-free survival [ Designated as safety issue: No ]

Secondary Outcome Measures:

Survival form study enrollment [ Designated as safety issue: No ]

Estimated Enrollment:	528
Study Start Date:	December 2005
Estimated Primary Completion Date:	November 2009 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Arm I: Active Comparator Patients receive vincristine IV over 1 minute once a week on day 1 in weeks 1-3, 7-9, and 13-15; doxorubicin hydrochloride IV over 15 minutes on days 1 and 2 in weeks 1, 7, and 13; cyclophosphamide IV over 1 hour on day 1 in weeks 1, 7, and 13; and ifosfamide IV over 1 hour and etoposide IV over 1 hour on days 1-5 in weeks 4, 10, and 16. Patients undergo local therapy comprising surgical resection in approximately week 18 and/or radiotherapy beginning in approximately week 19.	Drug: cyclophosphamide Given IV Drug: dexrazoxane hydrochloride Given IV Drug: doxorubicin hydrochloride Given IV Drug: etoposide Given IV Drug: ifosfamide Given IV Drug: vincristine sulfate Given IV Procedure: conventional surgery Patients undergo surgery in week 18 Procedure: radiation therapy Patients undero radiation therapy in week 19
Arm II: Experimental Patients receive vincristine IV over 1 minute once a week on day 1 in weeks 1-3, 7-9, and 13-16; topotecan hydrochloride IV over 30 minutes on days 1-5 in weeks 1 and 13; cyclophosphamide IV over 30 minutes on days 1-5 in weeks 1 and 13 and IV over 1 hour on day 1 in weeks 7 and 16; ifosfamide IV over 1 hour and etoposide IV over 1 hour on days 1-5 in weeks 4 and 10; and doxorubicin hydrochloride IV over 15 minutes on days 1 and 2 in weeks 7 and 16. Patients also undergo local therapy comprising surgical resection in approximately week 18 and/or radiotherapy beginning in approximately week 19. Patients then combination chemotherapy.	Drug: cyclophosphamide Given IV Drug: dexrazoxane hydrochloride Given IV Drug: doxorubicin hydrochloride Given IV Drug: etoposide Given IV Drug: ifosfamide Given IV Drug: topotecan hydrochloride Given IV Drug: vincristine sulfate Given IV Procedure: conventional surgery Patients undergo surgery in week 18 Procedure: radiation therapy Patients undero radiation therapy in week 19

Arms

Assigned Interventions

Arm I: Active Comparator

Patients receive vincristine IV over 1 minute once a week on day 1 in weeks 1-3, 7-9, and 13-15; doxorubicin hydrochloride IV over 15 minutes on days 1 and 2 in weeks 1, 7, and 13; cyclophosphamide IV over 1 hour on day 1 in weeks 1, 7, and 13; and ifosfamide IV over 1 hour and etoposide IV over 1 hour on days 1-5 in weeks 4, 10, and 16. Patients undergo local therapy comprising surgical resection in approximately week 18 and/or radiotherapy beginning in approximately week 19.

Drug: cyclophosphamide

Given IV

Drug: dexrazoxane hydrochloride

Given IV

Drug: doxorubicin hydrochloride

Given IV

Drug: etoposide

Given IV

Drug: ifosfamide

Given IV

Drug: vincristine sulfate

Given IV

Procedure: conventional surgery

Patients undergo surgery in week 18

Procedure: radiation therapy

Patients undero radiation therapy in week 19

Arm II: Experimental

Patients receive vincristine IV over 1 minute once a week on day 1 in weeks 1-3, 7-9, and 13-16; topotecan hydrochloride IV over 30 minutes on days 1-5 in weeks 1 and 13; cyclophosphamide IV over 30 minutes on days 1-5 in weeks 1 and 13 and IV over 1 hour on day 1 in weeks 7 and 16; ifosfamide IV over 1 hour and etoposide IV over 1 hour on days 1-5 in weeks 4 and 10; and doxorubicin hydrochloride IV over 15 minutes on days 1 and 2 in weeks 7 and 16. Patients also undergo local therapy comprising surgical resection in approximately week 18 and/or radiotherapy beginning in approximately week 19. Patients then combination chemotherapy.

Drug: cyclophosphamide

Given IV

Drug: dexrazoxane hydrochloride

Given IV

Drug: doxorubicin hydrochloride

Given IV

Drug: etoposide

Given IV

Drug: ifosfamide

Given IV

Drug: topotecan hydrochloride

Given IV

Drug: vincristine sulfate

Given IV

Procedure: conventional surgery

Patients undergo surgery in week 18

Procedure: radiation therapy

Patients undero radiation therapy in week 19

Detailed Description:

OBJECTIVES:

Primary

Compare the event-free and overall survival of patients with newly diagnosed localized Ewing's sarcoma treated with doxorubicin hydrochloride, cyclophosphamide, vincristine, etoposide, and ifosfamide with vs without topotecan hydrochloride.
Compare the side effects of these regimens in these patients.

Secondary

Evaluate initial tumor size as a prognostic factor for event-free survival of these patients.
Evaluate histological response as a prognostic factor for event-free survival of these patients.
Continue evaluation of biologic markers both as related to prognosis and as eventual therapeutic targets via encouraging concurrent enrollment on COG-AEWS02B1.
Evaluate radiologic response by positron emission tomography as a prognostic factor for event-free survival.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to age (≤ 17 vs ≥ 18 years of age) and primary tumor site (pelvic vs nonpelvic [including extra-osseous Ewing's sarcoma]). Patients are randomized to 1 of 2 treatment arms.

Arm I: Patients receive vincristine IV over 1 minute once a week on day 1 in weeks 1-3, 7-9, and 13-15; doxorubicin hydrochloride IV over 15 minutes on days 1 and 2 in weeks 1, 7, and 13; cyclophosphamide IV over 1 hour on day 1 in weeks 1, 7, and 13; and ifosfamide IV over 1 hour and etoposide IV over 1 hour on days 1-5 in weeks 4, 10, and 16. Patients undergo local therapy comprising surgical resection in approximately week 18 and/or radiotherapy beginning in approximately week 19. Patients then receive vincristine as above in weeks 19-21, 28-30, 34-36, 40-42, and 46-51; dexrazoxane hydrochloride IV over 15 minutes on days 1 and 2 and doxorubicin hydrochloride as above in weeks 19 and 28; cyclophosphamide as above in weeks 19, 28, 34, 40, 46, and 49; and ifosfamide and etoposide as above in weeks 22, 25, 31, 37, and 43.
Arm II: Patients receive vincristine IV over 1 minute once a week on day 1 in weeks 1-3, 7-9, and 13-16; topotecan hydrochloride IV over 30 minutes on days 1-5 in weeks 1 and 13; cyclophosphamide IV over 30 minutes on days 1-5 in weeks 1 and 13 and IV over 1 hour on day 1 in weeks 7 and 16; ifosfamide IV over 1 hour and etoposide IV over 1 hour on days 1-5 in weeks 4 and 10; and doxorubicin hydrochloride IV over 15 minutes on days 1 and 2 in weeks 7 and 16. Patients undergo local therapy comprising surgical resection in approximately week 18 and/or radiotherapy beginning in approximately week 19. Patients then receive vincristine as above in weeks 19-21, 28-33, 37-42, and 46-48; topotecan hydrochloride as above in weeks 19, 31, and 40; cyclophosphamide IV over 30 minutes in weeks 19, 31, and 40 and IV over 1 hour in weeks 28, 37, and 46; ifosfamide and etoposide as above in weeks 22, 25, 34, 43, and 49; dexrazoxane hydrochloride IV over 15 minutes on days 1 and 2 in weeks 37 and 46; and doxorubicin hydrochloride as above in weeks 28, 37, and 46.

After completion of study treatment, patients are followed periodically for 5 years.

PROJECTED ACCRUAL: A total of 528 patients will be accrued for this study.

Eligibility

Ages Eligible for Study:	up to 50 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

DISEASE CHARACTERISTICS:

Histologically and cytologically confirmed extracranial Ewing's sarcoma or primitive neuroectodermal tumor (PNET) of bone or soft tissue
- Chest wall tumors with ipsilateral pleural effusions, ipsilateral positive pleural fluid cytology, or ipsilateral pleural-based secondary tumor nodules allowed
  - Contralateral pleural effusions or pleural nodules are not eligible
- Tumor arising in the bony skull (extradural) are eligible
  - Tumors arising in the intradural soft tissue are not eligible
Newly diagnosed disease
- Only have had a biopsy of the primary tumor without an attempt at complete or partial resection
- Prior attempted or accomplished unplanned excision allowed provided adequate imaging was obtained prior to surgery AND resection considered incomplete and further local control required
No evidence of metastatic disease, defined as lesions discontinuous from the primary tumor, are not regional lymph nodes, and do not share a body cavity with the primary tumor
No evidence of metastatic lung disease by CT scan
- One pulmonary nodule > 1 cm in diameter OR > 1 nodule > 0.5 cm in diameter are considered evidence of pulmonary metastasis
- Solitary nodules 0.5-1.0 cm or multiple nodules 0.3-0.5 cm must be confirmed negative by biopsy
- Solitary nodules < 0.5 cm or multiple nodules < 0.3 cm not considered clear evidence of lung disease
No distant nodule disease
No esthesioneuroblastoma

PATIENT CHARACTERISTICS:

Performance status (PS) 0-2 (Karnofsky PS 50-100% for patients ≥ 16 years of age or Lansky PS 50-100% for patients < 16 years of age)
Creatinine clearance or radioisotope glomerular filtration rate (GFR) ≥ 70 mL/min
Bilirubin ≤ 1.5 times upper limit of normal (ULN)
AST or ALT < 2.5 times ULN
Shortening fraction ≥ 27% by EKG
Ejection fraction ≥ 50% by radionuclide angiogram
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

See Disease Characteristics
No prior radiotherapy
No prior chemotherapy

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00334867

Sponsors and Collaborators

Children's Oncology Group

National Cancer Institute (NCI)

Investigators

Study Chair:	Mason Bond, MD	Children's & Women's Hospital of British Columbia
Investigator:	Leo Mascarenhas, MD	Children's Hospital Los Angeles

More Information

Clinical trial summary from the National Cancer Institute's PDQ® database This link exits the ClinicalTrials.gov site

Study ID Numbers:	CDR0000483611, COG-AEWS0531
Study First Received:	June 7, 2006
Last Updated:	January 2, 2009
ClinicalTrials.gov Identifier:	NCT00334867
Health Authority:	Unspecified

Keywords provided by National Cancer Institute (NCI):

localized Ewing sarcoma/peripheral primitive neuroectodermal tumor

Study placed in the following topic categories:

Neuroectodermal Tumors, Primitive
Malignant mesenchymal tumor
Ewing's family of tumors
Vincristine
Osteosarcoma
Cyclophosphamide
Etoposide phosphate
Osteogenic sarcoma
Doxorubicin
Soft tissue sarcomas
Razoxane
Neuroectodermal Tumors

Neoplasms, Connective and Soft Tissue
Ifosfamide
Sarcoma, Ewing's
Ewing's sarcoma
Peripheral neuroectodermal tumor
Sarcoma
Neuroepithelioma
Topotecan
Etoposide
Neuroectodermal Tumors, Primitive, Peripheral
Isophosphamide mustard

Additional relevant MeSH terms:

Neoplasms by Histologic Type
Immunologic Factors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Mitosis Modulators
Physiological Effects of Drugs
Enzyme Inhibitors
Antimitotic Agents
Cardiovascular Agents
Antibiotics, Antineoplastic
Immunosuppressive Agents
Pharmacologic Actions

Neoplasms
Neoplasms, Bone Tissue
Therapeutic Uses
Tubulin Modulators
Myeloablative Agonists
Chelating Agents
Neoplasms, Connective Tissue
Antineoplastic Agents, Alkylating
Antirheumatic Agents
Antineoplastic Agents, Phytogenic
Alkylating Agents

ClinicalTrials.gov processed this record on January 16, 2009